Compendium of Cancer Genome Aberrations

HAEM5:Intravascular large B-cell lymphoma: Difference between revisions

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{{DISPLAYTITLE:Intravascular large B-cell lymphoma}}
{{DISPLAYTITLE:Intravascular large B-cell lymphoma}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
{{Under Construction}}


<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-03. The original page can be found at [[HAEM4:Intravascular Large B-cell Lymphoma]].
<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:Intravascular Large B-cell Lymphoma]].
}}</blockquote>
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<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)*==


Kate Berry, MBBS, BBus (Hons), Pathology Queensland
Kate Berry, MBBS, BBus (Hons), Pathology Queensland
==WHO Classification of Disease==


__TOC__
{| class="wikitable"
 
!Structure
==Cancer Category/Type==
!Disease
 
|-
Mature B-cell neoplasms
|Book
 
|Haematolymphoid Tumours (5th ed.)
==Cancer Sub-Classification / Subtype==
|-
 
|Category
Intravascular large B-cell lymphoma
|B-cell lymphoid proliferations and lymphomas
 
|-
==Definition / Description of Disease==
|Family
 
|Mature B-cell neoplasms
Intravascular large B-cell lymphoma (IVLBCL) is a rare, extranodal B-cell lymphoma in which there is selective growth of lymphoma cells within the lumina of small blood vessels, especially capillaries. Larger arteries and veins are not affected. <ref name=":0">Nakamura S, et al,, (2017). Intravascular large B-cell lymphoma, in World Health Organisation Classificaiton of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4<sup>th</sup> edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p330-334.</ref>
|-
|Type
|Large B-cell lymphomas
|-
|Subtype(s)
|Intravascular large B-cell lymphoma
|}


==Synonyms / Terminology==
==Related Terminology==


Obsolete: malignant angioendotheliomatosis; angioendotheliomatosis proliferans syndrome; intravascular lymphomatosis; angioendotheliotropic lymphoma.
==Epidemiology / Prevalence==
*IVLBCL is an extremely rare disease, with incidence estimated at 0.095 per million per year<ref>{{Cite journal|title=SEER Cancer Statistics Review, 1975-2017|url=https://seer.cancer.gov/csr/1975_2017/index.html|language=en}}</ref>
*The median age at diagnosis is 63-67 years<ref name=":0" /><ref name=":7">{{Cite journal|last=Geer|first=Marcus|last2=Roberts|first2=Emily|last3=Shango|first3=Maryann|last4=Till|first4=Brian G.|last5=Smith|first5=Stephen D.|last6=Abbas|first6=Hashim|last7=Hill|first7=Brian T.|last8=Kaplan|first8=Jason|last9=Barr|first9=Paul M.|date=2019-05|title=Multicentre retrospective study of intravascular large B‐cell lymphoma treated at academic institutions within the United States|url=https://onlinelibrary.wiley.com/doi/10.1111/bjh.15923|journal=British Journal of Haematology|language=en|pages=bjh.15923|doi=10.1111/bjh.15923|issn=0007-1048}}</ref>
*Incidence is not affected by sex
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|Acceptable
 
|N/A
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|EXAMPLE Cytopenias
|Angiotropic lymphoma; intravascular lymphomatosis
 
EXAMPLE Lymphocytosis (low level)
|}
|}


==Gene Rearrangements==


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues<ref name=":0" /> describes three patterns of clinical presentation observed in patients with IVLBCL. In the classic variant symptoms are related to the organ system primarily involved, usually cutaneous or neurological. Cutaneous manifestations are highly variable and include ecchymoses, blanchable erythematous macules and patches with telangiectasia<ref name=":1">{{Cite journal|last=Boonsakan|first=Paisarn|last2=Iamsumang|first2=Wimolsiri|last3=Chantrathammachart|first3=Pichika|last4=Chayavichitsilp|first4=Pamela|last5=Suchonwanit|first5=Poonkiat|last6=Rutnin|first6=Suthinee|date=2020-05-27|title=Prognostic Value of Concurrent Expression of C-MYC and BCL2 in Intravascular Large B-Cell Lymphoma: A 10-Year Retrospective Study|url=https://www.hindawi.com/journals/bmri/2020/1350820/|journal=BioMed Research International|language=en|volume=2020|pages=1–10|doi=10.1155/2020/1350820|issn=2314-6133|pmc=PMC7273482|pmid=32566654}}</ref> as well as tumours and ulcerated nodules. Approximately one third of patients show isolated cutaneous lesions and a similarly sized second group of patients presents with multi-organ involvement<ref name=":22">{{Cite journal|last=Ponzoni|first=Maurilio|last2=Campo|first2=Elias|last3=Nakamura|first3=Shigeo|date=2018-10-11|title=Intravascular large B-cell lymphoma: a chameleon with multiple faces and many masks|url=http://www.bloodjournal.org/lookup/doi/10.1182/blood-2017-04-737445|journal=Blood|language=en|volume=132|issue=15|pages=1561–1567|doi=10.1182/blood-2017-04-737445|issn=0006-4971}}</ref> including neurological symptoms, observed in 23.5-41% of cases<ref name=":7" /><ref name=":1" /> , which include impaired level of consciousness and heterogenous focal neurological deficits<ref name=":4" />. Patients tend to experience a rapid deterioration in performance status due to the aggressive nature of the disease<ref name=":22" />.
The haemophagocytic syndrome-associated variant, initially described by Murase et al<ref name=":8" />, and occurring primarily in Asian countries, presents with bone marrow involvement, fever, hepatosplenomegaly and thrombocytopoenia in the majority of patients<ref name=":22" />. Often, non-neoplastic haemophagocytic histiocytes can be identified in the bone marrow or peripheral blood<ref name=":22" />. Bone marrow haemophagocytosis is statistically associated with B symptoms, splenomegaly, higher CRP levels, lower albumin concentration, lower creatinine levels, and an absence of tumour cells in the peripheral blood<ref name=":8" />. Disease progression tends to be rapid and aggressive, with a median survival time of 2 to 8 months<ref name=":22" />. Fever of unknown origin is common in both variants, occurring in the majority of patients<ref name=":0" /><ref name=":7" /><ref name=":1" /><ref name=":4" />, as are night sweats and weight loss<ref name=":17" />. There is generally no tumour mass or lymphadenopathy suitable for biopsy or detectable using imaging<ref name=":0" />, causing diagnostic challenges and frequent false negatives during conventional staging. Radiological findings are often non-specific, but frequently include abnormalities if the central nervous system is imaged using MRI, including hyperintense lesions in the pons, non-specific white matter lesions, infarct-like lesions and meningeal enhancement<ref name=":4" />. Other findings include pleural effusion, ground glass appearance of lung parenchymal tissue on CT, splenomegaly, and abnormal FDG uptake in the adrenal glands and bone marrow on PET-CT<ref name=":4" />.
Other clinical features include:
·        Eastern Cooperative Oncology Group (ECOG) performance score ≥2 at diagnosis<ref name=":0" /><ref name=":4" />
·        Median International Prognostic Index score of 4 at diagnosis<ref name=":7" />
·        Ann Arbor stage IV at diagnosis (86%)<ref name=":7" />
·        Hepatomegaly or splenomegaly<ref name=":1" /><ref name=":8" />
·        Dyspnoea and hypoxaemia<ref name=":1" /><ref name=":4" />
·        Anaemia<ref name=":7" /><ref name=":1" /><ref name=":4" /><ref name=":8" />
·        Thrombocytopenia<ref name=":7" /><ref name=":1" /><ref name=":4" /><ref name=":8" />
·        Leukopoenia or leukocytosis<ref name=":1" />
·        Increased serum LDH<ref name=":7" /><ref name=":1" /><ref name=":4" />
·        Hypoalbuminaemia<ref name=":7" /><ref name=":4" />
·        Low level monoclonal immunoglobulin (approximately 14%)<ref name=":8" />
Additionally, an isolated cutaneous variant occurs almost exclusively in females. These individuals are of younger age than patients with other IVLBCL variants, and display a significantly better prognosis with less aggressive disease progression<ref name=":0" /><ref name=":3">{{Cite journal|last=Ponzoni|first=Maurilio|last2=Ferreri|first2=Andrés J.M.|last3=Campo|first3=Elías|last4=Facchetti|first4=Fabio|last5=Mazzucchelli|first5=Luca|last6=Yoshino|first6=Tadashi|last7=Murase|first7=Takuhei|last8=Pileri|first8=Stefano A.|last9=Doglioni|first9=Claudio|date=2007-07-20|title=Definition, Diagnosis, and Management of Intravascular Large B-Cell Lymphoma: Proposals and Perspectives From an International Consensus Meeting|url=http://ascopubs.org/doi/10.1200/JCO.2006.08.2313|journal=Journal of Clinical Oncology|language=en|volume=25|issue=21|pages=3168–3173|doi=10.1200/JCO.2006.08.2313|issn=0732-183X}}</ref>. These cutaneous lesions exhibit identical histological features to the classic variant, without involvement of other organ systems, and normal peripheral blood leukocyte and platelet counts<ref name=":22" />.
</blockquote>
==Sites of Involvement==
Almost any organ can be affected by IVLBCL including the thyroid, liver, pancreas, prostate and central nervous system<ref name=":4">{{Cite journal|last=Matsue|first=Kosei|last2=Abe|first2=Yoshiaki|last3=Narita|first3=Kentaro|last4=Kobayashi|first4=Hiroki|last5=Kitadate|first5=Akihiro|last6=Takeuchi|first6=Masami|last7=Miura|first7=Daisuke|last8=Takeuchi|first8=Kengo|date=2019-11|title=Diagnosis of intravascular large B cell lymphoma: novel insights into clinicopathological features from 42 patients at a single institution over 20 years|url=https://onlinelibrary.wiley.com/doi/10.1111/bjh.16081|journal=British Journal of Haematology|language=en|volume=187|issue=3|pages=328–336|doi=10.1111/bjh.16081|issn=0007-1048|pmc=PMC6900202|pmid=31267524}}</ref>. Bone marrow involvement is observed in 33-67% of patients<ref name=":7" /><ref name=":4" /><ref name=":6">{{Cite journal|last=Suehara|first=Yasuhito|last2=Sakata-Yanagimoto|first2=Mamiko|last3=Hattori|first3=Keiichiro|last4=Nanmoku|first4=Toru|last5=Itoh|first5=Takayoshi|last6=Kaji|first6=Daisuke|last7=Yamamoto|first7=Go|last8=Abe|first8=Yoshiaki|last9=Narita|first9=Kentaro|date=2018-06|title=Liquid biopsy for the identification of intravascular large B-cell lymphoma|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2017.178830|journal=Haematologica|language=en|volume=103|issue=6|pages=e241–e244|doi=10.3324/haematol.2017.178830|issn=0390-6078|pmc=PMC6058794|pmid=29472348}}</ref><ref name=":17">{{Cite journal|last=Schrader|first=Anne M. R.|last2=Jansen|first2=Patty M.|last3=Willemze|first3=Rein|last4=Vermeer|first4=Maarten H.|last5=Cleton-Jansen|first5=Anne-Marie|last6=Somers|first6=Sebastiaan F.|last7=Veelken|first7=Hendrik|last8=van Eijk|first8=Ronald|last9=Kraan|first9=Willem|date=2018-05-03|title=High prevalence of MYD88 and CD79B mutations in intravascular large B-cell lymphoma|url=https://ashpublications.org/blood/article/131/18/2086/36715/High-prevalence-of-MYD88-and-CD79B-mutations-in|journal=Blood|language=en|volume=131|issue=18|pages=2086–2089|doi=10.1182/blood-2017-12-822817|issn=0006-4971}}</ref>, but this number increases to 93% in patients that present with organomegaly. Within the bone marrow the malignant cells are often limited to the sinusoids and merge with the surrounding haematopoietic elements, making histological recognition difficult. Peripheral blood involvement occurs in 5-12% of cases<ref name=":4" /><ref name=":3" /> and the lymph nodes are generally not involved<ref name=":0" />. Tumour cells are often observed in the subcutaneous tissues, even in the absence of macroscopic skin lesions<ref name=":5" /><ref name=":7" />. Extravascular lymphoma infiltration is rare, but may be observed, and can be extensive in the absence of treatment, such as in cases diagnosed at autopsy<ref name=":4" />.
==Morphologic Features==
IVLBCL can show variable cytomorphology. Most commonly the lymphoma cells are large with vesicular nuclei, prominent nucleoli and plentiful mitotic figures<ref name=":0" /><ref name=":3" /><ref name=":8">{{Cite journal|last=Murase|first=Takuhei|last2=Yamaguchi|first2=Motoko|last3=Suzuki|first3=Ritsuro|last4=Okamoto|first4=Masataka|last5=Sato|first5=Yumiko|last6=Tamaru|first6=Jun-ichi|last7=Kojima|first7=Masaru|last8=Miura|first8=Ikuo|last9=Mori|first9=Naoyoshi|date=2007-01-15|title=Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5|url=https://ashpublications.org/blood/article/109/2/478/23520/Intravascular-large-Bcell-lymphoma-IVLBCL-a|journal=Blood|language=en|volume=109|issue=2|pages=478–485|doi=10.1182/blood-2006-01-021253|issn=0006-4971}}</ref>. Less commonly, they may show coarse chromatin and irregular or indented nuclei<ref name=":3" />. By definition, the lymphoma involves the lumina of small to intermediate sized blood vessels<ref name=":0" />, and this occurs within many organs, including the central nervous system. Sinusoidal involvement (of the liver, spleen and bone marrow) and focal extravasation of tumour cells into surrounding tissues may be seen<ref name=":0" /><ref name=":3" />.  Haemophagocytosis by benign-appearing histiocytes occurs in the haemophagocytic syndrome-associated variant<ref name=":3" />, in approximately 12% of  IVLBCL patients overall<ref name=":7" />.
==Immunophenotype==
Intravascular large B cell lymphoma is overwhelmingly a neoplasm of  activated B-cell (ABC) type, rather than germinal centre (GCB) type, when classified by immunohistochemistry using the Hans algorithm<ref name=":7" /><ref>{{Cite journal|last=Hans|first=C. P.|date=2004-01-01|title=Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray|url=http://dx.doi.org/10.1182/blood-2003-05-1545|journal=Blood|volume=103|issue=1|pages=275–282|doi=10.1182/blood-2003-05-1545|issn=0006-4971}}</ref><ref name=":2">{{Cite journal|last=Shimada|first=Kazuyuki|last2=Yoshida|first2=Kenichi|last3=Suzuki|first3=Yasuhiro|last4=Iriyama|first4=Chisako|last5=Inoue|first5=Yoshikage|last6=Sanada|first6=Masashi|last7=Kataoka|first7=Keisuke|last8=Yuge|first8=Masaaki|last9=Takagi|first9=Yusuke|date=2021-03-18|title=Frequent genetic alterations in immune checkpoint–related genes in intravascular large B-cell lymphoma|url=https://ashpublications.org/blood/article/137/11/1491/474768/Frequent-genetic-alterations-in-immune-checkpoint|journal=Blood|language=en|volume=137|issue=11|pages=1491–1502|doi=10.1182/blood.2020007245|issn=0006-4971|pmc=PMC7976508|pmid=33512416}}</ref><ref name=":6" />. Pan B-cell markers are almost universally expressed by IVLBCL, and MUM1 and IgM expression can be seen in up to 95% and 91% of cases, respectively<ref name=":8" /><ref name=":17" />. In up to 50% of cases there is aberrant expression of CD5<ref name=":0" /><ref name=":7" /><ref name=":4" /><ref name=":8" />. The tumour cells are usually negative for CD23, CD10 and BCL6, and EBER-ISH is negative.


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"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!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
|-
|-
|Positive (universal)||CD20, CD79a
|<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).
|-
|-
|Positive (usually)||CD5 (38-50%)<ref name=":7" /><ref name=":0" /><ref name=":4" /><ref name=":8" />, MYC (63-68%)<ref name=":7" /><ref name=":17" />, BCL2 (80-96%)<ref name=":7" /><ref name=":8" /><ref name=":17" />, CD19(85%)<ref name=":8" />, MUM1(75-95%)<ref name=":17" /><ref name=":8" />, Igκ, IgM(91%)<ref name=":17" />
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|Negative (universal)||EBER-ISH, Cyclin D1, CD30
|<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>
 
''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).
|-
|-
|Negative (usually)||CD23(96%)<ref name=":8" />, CD10(92%)<ref name=":0" /><ref name=":17" /><ref name=":8" />, BCL-6(42-74%)<ref name=":17" /><ref name=":8" />
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|}
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''


==Chromosomal Rearrangements (Gene Fusions)==


Put your text here and fill in the table
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.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>


{| class="wikitable sortable"
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
!Diagnostic Significance (Yes, No or Unknown)
|<span class="blue-text">EXAMPLE:</span> N/A
!Prognostic Significance (Yes, No or Unknown)
|<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.
!Therapeutic Significance (Yes, No or Unknown)
|<span class="blue-text">EXAMPLE:</span> N/A
!Notes
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
|
EXAMPLE 30% (add reference)
|
|Yes
|
|No
|
|Yes
|
|EXAMPLE
|
 
|
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).
|
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>


Due to limited data, the prevalence of chromosomal rearrangements in IVLBCL are incompletely described. However, multiple case reports and small series exist describing an array of gene fusions, many of which include the IgH gene, located at 14q32<ref name=":9">{{Cite journal|last=Kobayashi|first=Taishi|last2=Ohno|first2=Hitoshi|date=2011|title=Intravascular Large B-Cell Lymphoma Associated with t(14;19)(q32;q13) Translocation|url=http://www.jstage.jst.go.jp/article/internalmedicine/50/18/50_18_2007/_article|journal=Internal Medicine|language=en|volume=50|issue=18|pages=2007–2010|doi=10.2169/internalmedicine.50.5706|issn=0918-2918}}</ref><ref name=":10">{{Cite journal|last=Murase|first=Takuhei|last2=Nakamura|first2=Shigeo|last3=Kawauchi|first3=Kiyotaka|last4=Matsuzaki|first4=Hiromitsu|last5=Sakai|first5=Chikara|last6=Inaba|first6=Tohru|last7=Nasu|first7=Kaori|last8=Tashiro|first8=Kazuhiro|last9=Suchi|first9=Taizan|date=2000-12|title=An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma associated with haemophagocytic syndrome|url=http://dx.doi.org/10.1111/j.1365-2141.2000.02426.x|journal=British Journal of Haematology|volume=111|issue=3|pages=826–834|doi=10.1111/j.1365-2141.2000.02426.x|issn=0007-1048}}</ref><ref name=":11">{{Cite journal|last=Rashid|first=Rumana|last2=Johnson|first2=Roderick J.|last3=Morris|first3=Stephen|last4=Dickinson|first4=Helen|last5=Czyz|first5=Jarek|last6=O'Connor|first6=Sheila J.M.|last7=Owen|first7=Roger G.|date=2006-12|title=Intravascular large B-cell lymphoma associated with a near-tetraploid karyotype, rearrangement of BCL6, and a t(11;14)(q13;q32)|url=https://linkinghub.elsevier.com/retrieve/pii/S0165460806004511|journal=Cancer Genetics and Cytogenetics|language=en|volume=171|issue=2|pages=101–104|doi=10.1016/j.cancergencyto.2006.07.018}}</ref><ref name=":13">{{Cite journal|last=Khoury|first=Haytham|last2=Lestou|first2=Valia S|last3=Gascoyne|first3=Randy D|last4=Bruyere|first4=Helene|last5=Li|first5=Charles H|last6=Nantel|first6=Stephen H|last7=Dalal|first7=Bakul I|last8=Naiman|first8=Shelly C|last9=Horsman|first9=Douglas E|date=2003-07|title=Multicolor Karyotyping and Clinicopathological Analysis of Three Intravascular Lymphoma Cases|url=http://www.nature.com/doifinder/10.1097/01.MP.0000077515.68734.85|journal=Modern Pathology|volume=16|issue=7|pages=716–724|doi=10.1097/01.MP.0000077515.68734.85|issn=0893-3952}}</ref><ref name=":15">{{Cite journal|last=Klairmont|first=Matthew M|last2=Cheng|first2=Jinjun|last3=Martin|first3=Mike G|last4=Gradowski|first4=Joel F|date=2018-05-31|title=Recurrent Cytogenetic Abnormalities in Intravascular Large B-Cell Lymphoma|url=https://academic.oup.com/ajcp/article/150/1/18/4996033|journal=American Journal of Clinical Pathology|language=en|volume=150|issue=1|pages=18–26|doi=10.1093/ajcp/aqy023|issn=0002-9173}}</ref><ref name=":16">{{Cite journal|last=Cui|first=Jing|last2=Liu|first2=Qun|last3=Cheng|first3=Yuxia|last4=Chen|first4=Shaoyu|last5=Sun|first5=Qing|date=2014-03|title=An intravascular large B-cell lymphoma with a t(3;14)(q27;q32) translocation|url=http://jcp.bmj.com/lookup/doi/10.1136/jclinpath-2013-201980|journal=Journal of Clinical Pathology|language=en|volume=67|issue=3|pages=279–281|doi=10.1136/jclinpath-2013-201980|issn=0021-9746}}</ref>, rearrangements of which constitute a very common cytogenetic abnormality in DLBCL<ref>{{Cite journal|last=Cigudosa|first=Juan C.|last2=Parsa|first2=Nasser Z.|last3=Louie|first3=Diane C.|last4=Filippa|first4=Daniel A.|last5=Jhanwar|first5=Suresh C.|last6=Johansson|first6=Bertil|last7=Mitelman|first7=Felix|last8=Chaganti|first8=R.S.K.|date=1999-06|title=Cytogenetic analysis of 363 consecutively ascertained diffuse large B-cell lymphomas|url=http://dx.doi.org/10.1002/(sici)1098-2264(199906)25:2<123::aid-gcc8>3.0.co;2-4|journal=Genes, Chromosomes and Cancer|volume=25|issue=2|pages=123–133|doi=10.1002/(sici)1098-2264(199906)25:2<123::aid-gcc8>3.0.co;2-4|issn=1045-2257}}</ref>.  The t(14;19)(q32;q13) translocation, involving the BCL3 gene at 19q13, is a recurrent translocation in chronic lymphocytic leukaemia (CLL) and confers an adverse prognosis with a higher probability of requiring therapy and shorter overall survival<ref>{{Cite journal|last=Fang|first=Hong|last2=Reichard|first2=Kaaren K.|last3=Rabe|first3=Kari G.|last4=Hanson|first4=Curtis A.|last5=Call|first5=Timothy G.|last6=Ding|first6=Wei|last7=Kenderian|first7=Saad S.|last8=Muchtar|first8=Eli|last9=Schwager|first9=Susan M.|date=2019-03|title=IGH translocations in chronic lymphocytic leukemia: Clinicopathologic features and clinical outcomes|url=https://onlinelibrary.wiley.com/doi/10.1002/ajh.25385|journal=American Journal of Hematology|language=en|volume=94|issue=3|pages=338–345|doi=10.1002/ajh.25385|pmc=PMC6625355|pmid=30575108}}</ref>. However, in CLL the translocation is associated with over-expression of BCL3, which is involved in the regulation of the NF-κβ signalling pathway and is a suggested proto-oncogene. In one confirmed<ref name=":9" />  and one possible <ref name=":14">{{Cite journal|last=Yamamoto|first=Katsuya|last2=Nakamura|first2=Yuichi|last3=Arai|first3=Honoka|last4=Aoyagi|first4=Masakuni|last5=Saito|first5=Kenji|last6=Furusawa|first6=Shinpei|last7=Mitani|first7=Kinuko|date=2001-10|title=Translocation (14;19)(q32;q13) detected by spectral karyotyping and lack of BCL3 rearrangement in CD5-positive B-cell lymphoma associated with hemophagocytic syndrome|url=https://linkinghub.elsevier.com/retrieve/pii/S0165460801004666|journal=Cancer Genetics and Cytogenetics|language=en|volume=130|issue=1|pages=38–41|doi=10.1016/S0165-4608(01)00466-6}}</ref> IVLBCL case with t(14;19)(q32;q13) in the literature, BCL3 overexpression was not identified by immunohistochemistry and Southern blot analysis, respectively, suggesting the role of a second oncogene at 19q13 in these tumours. In a karyotypic analysis of three cases of IVLBCL and a literature review, Khoury et al<ref name=":13" /> described case reports of breakpoints involving BCL6, CMYC, PAX5, BCL1, BCL2 and BCL3, all gene loci which have been implicated in other haematological diseases, but more data is required to determine if IVLBCL harbours the same recurrent translocations as other B-cell malignancies.
Due to limited data, the prevalence of chromosomal rearrangements in IVLBCL are incompletely described. However, multiple case reports and small series exist describing an array of gene fusions, many of which include the IgH gene, located at 14q32<ref name=":9">{{Cite journal|last=Kobayashi|first=Taishi|last2=Ohno|first2=Hitoshi|date=2011|title=Intravascular Large B-Cell Lymphoma Associated with t(14;19)(q32;q13) Translocation|url=http://www.jstage.jst.go.jp/article/internalmedicine/50/18/50_18_2007/_article|journal=Internal Medicine|language=en|volume=50|issue=18|pages=2007–2010|doi=10.2169/internalmedicine.50.5706|issn=0918-2918}}</ref><ref name=":10">{{Cite journal|last=Murase|first=Takuhei|last2=Nakamura|first2=Shigeo|last3=Kawauchi|first3=Kiyotaka|last4=Matsuzaki|first4=Hiromitsu|last5=Sakai|first5=Chikara|last6=Inaba|first6=Tohru|last7=Nasu|first7=Kaori|last8=Tashiro|first8=Kazuhiro|last9=Suchi|first9=Taizan|date=2000-12|title=An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma associated with haemophagocytic syndrome|url=http://dx.doi.org/10.1111/j.1365-2141.2000.02426.x|journal=British Journal of Haematology|volume=111|issue=3|pages=826–834|doi=10.1111/j.1365-2141.2000.02426.x|issn=0007-1048}}</ref><ref name=":11">{{Cite journal|last=Rashid|first=Rumana|last2=Johnson|first2=Roderick J.|last3=Morris|first3=Stephen|last4=Dickinson|first4=Helen|last5=Czyz|first5=Jarek|last6=O'Connor|first6=Sheila J.M.|last7=Owen|first7=Roger G.|date=2006-12|title=Intravascular large B-cell lymphoma associated with a near-tetraploid karyotype, rearrangement of BCL6, and a t(11;14)(q13;q32)|url=https://linkinghub.elsevier.com/retrieve/pii/S0165460806004511|journal=Cancer Genetics and Cytogenetics|language=en|volume=171|issue=2|pages=101–104|doi=10.1016/j.cancergencyto.2006.07.018}}</ref><ref name=":13">{{Cite journal|last=Khoury|first=Haytham|last2=Lestou|first2=Valia S|last3=Gascoyne|first3=Randy D|last4=Bruyere|first4=Helene|last5=Li|first5=Charles H|last6=Nantel|first6=Stephen H|last7=Dalal|first7=Bakul I|last8=Naiman|first8=Shelly C|last9=Horsman|first9=Douglas E|date=2003-07|title=Multicolor Karyotyping and Clinicopathological Analysis of Three Intravascular Lymphoma Cases|url=http://www.nature.com/doifinder/10.1097/01.MP.0000077515.68734.85|journal=Modern Pathology|volume=16|issue=7|pages=716–724|doi=10.1097/01.MP.0000077515.68734.85|issn=0893-3952}}</ref><ref name=":15">{{Cite journal|last=Klairmont|first=Matthew M|last2=Cheng|first2=Jinjun|last3=Martin|first3=Mike G|last4=Gradowski|first4=Joel F|date=2018-05-31|title=Recurrent Cytogenetic Abnormalities in Intravascular Large B-Cell Lymphoma|url=https://academic.oup.com/ajcp/article/150/1/18/4996033|journal=American Journal of Clinical Pathology|language=en|volume=150|issue=1|pages=18–26|doi=10.1093/ajcp/aqy023|issn=0002-9173}}</ref><ref name=":16">{{Cite journal|last=Cui|first=Jing|last2=Liu|first2=Qun|last3=Cheng|first3=Yuxia|last4=Chen|first4=Shaoyu|last5=Sun|first5=Qing|date=2014-03|title=An intravascular large B-cell lymphoma with a t(3;14)(q27;q32) translocation|url=http://jcp.bmj.com/lookup/doi/10.1136/jclinpath-2013-201980|journal=Journal of Clinical Pathology|language=en|volume=67|issue=3|pages=279–281|doi=10.1136/jclinpath-2013-201980|issn=0021-9746}}</ref>, rearrangements of which constitute a very common cytogenetic abnormality in DLBCL<ref>{{Cite journal|last=Cigudosa|first=Juan C.|last2=Parsa|first2=Nasser Z.|last3=Louie|first3=Diane C.|last4=Filippa|first4=Daniel A.|last5=Jhanwar|first5=Suresh C.|last6=Johansson|first6=Bertil|last7=Mitelman|first7=Felix|last8=Chaganti|first8=R.S.K.|date=1999-06|title=Cytogenetic analysis of 363 consecutively ascertained diffuse large B-cell lymphomas|url=http://dx.doi.org/10.1002/(sici)1098-2264(199906)25:2<123::aid-gcc8>3.0.co;2-4|journal=Genes, Chromosomes and Cancer|volume=25|issue=2|pages=123–133|doi=10.1002/(sici)1098-2264(199906)25:2<123::aid-gcc8>3.0.co;2-4|issn=1045-2257}}</ref>.  The t(14;19)(q32;q13) translocation, involving the BCL3 gene at 19q13, is a recurrent translocation in chronic lymphocytic leukaemia (CLL) and confers an adverse prognosis with a higher probability of requiring therapy and shorter overall survival<ref>{{Cite journal|last=Fang|first=Hong|last2=Reichard|first2=Kaaren K.|last3=Rabe|first3=Kari G.|last4=Hanson|first4=Curtis A.|last5=Call|first5=Timothy G.|last6=Ding|first6=Wei|last7=Kenderian|first7=Saad S.|last8=Muchtar|first8=Eli|last9=Schwager|first9=Susan M.|date=2019-03|title=IGH translocations in chronic lymphocytic leukemia: Clinicopathologic features and clinical outcomes|url=https://onlinelibrary.wiley.com/doi/10.1002/ajh.25385|journal=American Journal of Hematology|language=en|volume=94|issue=3|pages=338–345|doi=10.1002/ajh.25385|pmc=PMC6625355|pmid=30575108}}</ref>. However, in CLL the translocation is associated with over-expression of BCL3, which is involved in the regulation of the NF-κβ signalling pathway and is a suggested proto-oncogene. In one confirmed<ref name=":9" />  and one possible <ref name=":14">{{Cite journal|last=Yamamoto|first=Katsuya|last2=Nakamura|first2=Yuichi|last3=Arai|first3=Honoka|last4=Aoyagi|first4=Masakuni|last5=Saito|first5=Kenji|last6=Furusawa|first6=Shinpei|last7=Mitani|first7=Kinuko|date=2001-10|title=Translocation (14;19)(q32;q13) detected by spectral karyotyping and lack of BCL3 rearrangement in CD5-positive B-cell lymphoma associated with hemophagocytic syndrome|url=https://linkinghub.elsevier.com/retrieve/pii/S0165460801004666|journal=Cancer Genetics and Cytogenetics|language=en|volume=130|issue=1|pages=38–41|doi=10.1016/S0165-4608(01)00466-6}}</ref> IVLBCL case with t(14;19)(q32;q13) in the literature, BCL3 overexpression was not identified by immunohistochemistry and Southern blot analysis, respectively, suggesting the role of a second oncogene at 19q13 in these tumours. In a karyotypic analysis of three cases of IVLBCL and a literature review, Khoury et al<ref name=":13" /> described case reports of breakpoints involving BCL6, CMYC, PAX5, BCL1, BCL2 and BCL3, all gene loci which have been implicated in other haematological diseases, but more data is required to determine if IVLBCL harbours the same recurrent translocations as other B-cell malignancies.


There is insufficient data to comment on the prevalence of high-grade B-cell lymphoma (in which there are concurrent translocations of MYC as well as BCL2 and/or BCL6) amongst IVLBCL cases, but given that the vast majority of high-grade B-cell lymphomas are of germinal centre B-cell type<ref>{{Cite journal|last=Akyurek|first=Nalan|last2=Uner|first2=Aysegul|last3=Benekli|first3=Mustafa|last4=Barista|first4=Ibrahim|date=2012-09-01|title=Prognostic significance of MYC , BCL2 , and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab: MYC , BCL2 , BCL6 Rearrangements in DLBCL|url=https://onlinelibrary.wiley.com/doi/10.1002/cncr.27396|journal=Cancer|language=en|volume=118|issue=17|pages=4173–4183|doi=10.1002/cncr.27396}}</ref><ref>{{Cite journal|last=Copie-Bergman|first=Christiane|last2=Cuillière-Dartigues|first2=Peggy|last3=Baia|first3=Maryse|last4=Briere|first4=Josette|last5=Delarue|first5=Richard|last6=Canioni|first6=Danielle|last7=Salles|first7=Gilles|last8=Parrens|first8=Marie|last9=Belhadj|first9=Karim|date=2015-11-26|title=MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study|url=https://ashpublications.org/blood/article/126/22/2466/34616/MYCIG-rearrangements-are-negative-predictors-of|journal=Blood|language=en|volume=126|issue=22|pages=2466–2474|doi=10.1182/blood-2015-05-647602|issn=0006-4971}}</ref>, and small series have failed to identify MYC rearrangements by break-apart FISH<ref name=":17" /> ,it can be assumed to be low.
There is insufficient data to comment on the prevalence of high-grade B-cell lymphoma (in which there are concurrent translocations of MYC as well as BCL2 and/or BCL6) amongst IVLBCL cases, but given that the vast majority of high-grade B-cell lymphomas are of germinal centre B-cell type<ref>{{Cite journal|last=Akyurek|first=Nalan|last2=Uner|first2=Aysegul|last3=Benekli|first3=Mustafa|last4=Barista|first4=Ibrahim|date=2012-09-01|title=Prognostic significance of MYC , BCL2 , and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab: MYC , BCL2 , BCL6 Rearrangements in DLBCL|url=https://onlinelibrary.wiley.com/doi/10.1002/cncr.27396|journal=Cancer|language=en|volume=118|issue=17|pages=4173–4183|doi=10.1002/cncr.27396}}</ref><ref>{{Cite journal|last=Copie-Bergman|first=Christiane|last2=Cuillière-Dartigues|first2=Peggy|last3=Baia|first3=Maryse|last4=Briere|first4=Josette|last5=Delarue|first5=Richard|last6=Canioni|first6=Danielle|last7=Salles|first7=Gilles|last8=Parrens|first8=Marie|last9=Belhadj|first9=Karim|date=2015-11-26|title=MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study|url=https://ashpublications.org/blood/article/126/22/2466/34616/MYCIG-rearrangements-are-negative-predictors-of|journal=Blood|language=en|volume=126|issue=22|pages=2466–2474|doi=10.1182/blood-2015-05-647602|issn=0006-4971}}</ref>, and small series have failed to identify MYC rearrangements by break-apart FISH<ref name=":17">{{Cite journal|last=Schrader|first=Anne M. R.|last2=Jansen|first2=Patty M.|last3=Willemze|first3=Rein|last4=Vermeer|first4=Maarten H.|last5=Cleton-Jansen|first5=Anne-Marie|last6=Somers|first6=Sebastiaan F.|last7=Veelken|first7=Hendrik|last8=van Eijk|first8=Ronald|last9=Kraan|first9=Willem|date=2018-05-03|title=High prevalence of MYD88 and CD79B mutations in intravascular large B-cell lymphoma|url=https://ashpublications.org/blood/article/131/18/2086/36715/High-prevalence-of-MYD88-and-CD79B-mutations-in|journal=Blood|language=en|volume=131|issue=18|pages=2086–2089|doi=10.1182/blood-2017-12-822817|issn=0006-4971}}</ref> ,it can be assumed to be low.
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>




<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
* Gene Mutations (SNV/INDEL)}}</blockquote>


Intravascular large B cell lymphoma is an aggressive disease, with median overall survival of 105 months and a 5 year survival rate of 46-84%<ref name=":4" /><ref>{{Cite journal|last=Rajyaguru|first=Devalkumar J.|last2=Bhaskar|first2=Chaithanya|last3=Borgert|first3=Andrew J.|last4=Smith|first4=Angela|last5=Parsons|first5=Benjamin|date=2017-09-02|title=Intravascular large B-cell lymphoma in the United States (US): a population-based study using Surveillance, Epidemiology, and End Results program and National Cancer Database*|url=https://www.tandfonline.com/doi/full/10.1080/10428194.2017.1287363|journal=Leukemia & Lymphoma|language=en|volume=58|issue=9|pages=2080–2088|doi=10.1080/10428194.2017.1287363|issn=1042-8194}}</ref><ref name=":2" />. Commonly used treatment regimens include R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) +/- high dose methotrexate, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), R-CODOX-M (rituximab, cyclophosphamide, cytarabine, doxorubicin, vincristine, methotrexate) and R-IVAC (rituximab, ifosfamide, cytarabine, etoposide)<ref name=":7" />.Patients with the cutaneous variant have significantly longer overall survival, independent of their International Prognostic Index<ref name=":3" /><ref name=":17" />. The effect of molecular aberrations on overall survival is difficult to define, both because of the limited data available and since a significant percentage of IVLBCL cases are diagnosed at a very advanced stage, or at autopsy. However in a small series of cases mutational status of MYD88 and CD79B did not significantly influence disease-specific overall survival, and were detected in patients with both the systemic and isolated cutaneous variants of the disease<ref name=":17" />. Several possible therapeutic targets exist amongst identified recurrent mutations. The high prevalence of PD-L2 and PD-L2 aberrations suggests a possible therapeutic role for immune checkpoint inhibitors <ref name=":2" /> and the presence of MYD88 and CD79B mutations suggests that there may be a role for drugs targeting NFκβ signalling, such as ibrutinib<ref name=":17" />. TNFAIP3 loss has been shown to be associated with ibrutinib resistance in ABC-type DLBCL<ref name=":21" /> and the implications of this mutation on treatment in IVLBCL requires further research. Finally, the most commonly detected MYD88 mutant, L265P,  can form a stable protein signalling complex containing IRAK1, a serine/threonine protein kinase, providing a possible therapeutic target in the form of IRAK4 inhibitors<ref name=":20" />.
Intravascular large B cell lymphoma is an aggressive disease, with median overall survival of 105 months and a 5 year survival rate of 46-84%<ref name=":4">{{Cite journal|last=Matsue|first=Kosei|last2=Abe|first2=Yoshiaki|last3=Narita|first3=Kentaro|last4=Kobayashi|first4=Hiroki|last5=Kitadate|first5=Akihiro|last6=Takeuchi|first6=Masami|last7=Miura|first7=Daisuke|last8=Takeuchi|first8=Kengo|date=2019-11|title=Diagnosis of intravascular large B cell lymphoma: novel insights into clinicopathological features from 42 patients at a single institution over 20 years|url=https://onlinelibrary.wiley.com/doi/10.1111/bjh.16081|journal=British Journal of Haematology|language=en|volume=187|issue=3|pages=328–336|doi=10.1111/bjh.16081|issn=0007-1048|pmc=PMC6900202|pmid=31267524}}</ref><ref>{{Cite journal|last=Rajyaguru|first=Devalkumar J.|last2=Bhaskar|first2=Chaithanya|last3=Borgert|first3=Andrew J.|last4=Smith|first4=Angela|last5=Parsons|first5=Benjamin|date=2017-09-02|title=Intravascular large B-cell lymphoma in the United States (US): a population-based study using Surveillance, Epidemiology, and End Results program and National Cancer Database*|url=https://www.tandfonline.com/doi/full/10.1080/10428194.2017.1287363|journal=Leukemia & Lymphoma|language=en|volume=58|issue=9|pages=2080–2088|doi=10.1080/10428194.2017.1287363|issn=1042-8194}}</ref><ref name=":2">{{Cite journal|last=Shimada|first=Kazuyuki|last2=Yoshida|first2=Kenichi|last3=Suzuki|first3=Yasuhiro|last4=Iriyama|first4=Chisako|last5=Inoue|first5=Yoshikage|last6=Sanada|first6=Masashi|last7=Kataoka|first7=Keisuke|last8=Yuge|first8=Masaaki|last9=Takagi|first9=Yusuke|date=2021-03-18|title=Frequent genetic alterations in immune checkpoint–related genes in intravascular large B-cell lymphoma|url=https://ashpublications.org/blood/article/137/11/1491/474768/Frequent-genetic-alterations-in-immune-checkpoint|journal=Blood|language=en|volume=137|issue=11|pages=1491–1502|doi=10.1182/blood.2020007245|issn=0006-4971|pmc=PMC7976508|pmid=33512416}}</ref>. Commonly used treatment regimens include R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) +/- high dose methotrexate, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), R-CODOX-M (rituximab, cyclophosphamide, cytarabine, doxorubicin, vincristine, methotrexate) and R-IVAC (rituximab, ifosfamide, cytarabine, etoposide)<ref name=":7">{{Cite journal|last=Geer|first=Marcus|last2=Roberts|first2=Emily|last3=Shango|first3=Maryann|last4=Till|first4=Brian G.|last5=Smith|first5=Stephen D.|last6=Abbas|first6=Hashim|last7=Hill|first7=Brian T.|last8=Kaplan|first8=Jason|last9=Barr|first9=Paul M.|date=2019-05|title=Multicentre retrospective study of intravascular large B‐cell lymphoma treated at academic institutions within the United States|url=https://onlinelibrary.wiley.com/doi/10.1111/bjh.15923|journal=British Journal of Haematology|language=en|pages=bjh.15923|doi=10.1111/bjh.15923|issn=0007-1048}}</ref>.Patients with the cutaneous variant have significantly longer overall survival, independent of their International Prognostic Index<ref name=":3">{{Cite journal|last=Ponzoni|first=Maurilio|last2=Ferreri|first2=Andrés J.M.|last3=Campo|first3=Elías|last4=Facchetti|first4=Fabio|last5=Mazzucchelli|first5=Luca|last6=Yoshino|first6=Tadashi|last7=Murase|first7=Takuhei|last8=Pileri|first8=Stefano A.|last9=Doglioni|first9=Claudio|date=2007-07-20|title=Definition, Diagnosis, and Management of Intravascular Large B-Cell Lymphoma: Proposals and Perspectives From an International Consensus Meeting|url=http://ascopubs.org/doi/10.1200/JCO.2006.08.2313|journal=Journal of Clinical Oncology|language=en|volume=25|issue=21|pages=3168–3173|doi=10.1200/JCO.2006.08.2313|issn=0732-183X}}</ref><ref name=":17" />. The effect of molecular aberrations on overall survival is difficult to define, both because of the limited data available and since a significant percentage of IVLBCL cases are diagnosed at a very advanced stage, or at autopsy. However in a small series of cases mutational status of MYD88 and CD79B did not significantly influence disease-specific overall survival, and were detected in patients with both the systemic and isolated cutaneous variants of the disease<ref name=":17" />. Several possible therapeutic targets exist amongst identified recurrent mutations. The high prevalence of PD-L2 and PD-L2 aberrations suggests a possible therapeutic role for immune checkpoint inhibitors <ref name=":2" /> and the presence of MYD88 and CD79B mutations suggests that there may be a role for drugs targeting NFκβ signalling, such as ibrutinib<ref name=":17" />. TNFAIP3 loss has been shown to be associated with ibrutinib resistance in ABC-type DLBCL<ref name=":21" /> and the implications of this mutation on treatment in IVLBCL requires further research. Finally, the most commonly detected MYD88 mutant, L265P,  can form a stable protein signalling complex containing IRAK1, a serine/threonine protein kinase, providing a possible therapeutic target in the form of IRAK4 inhibitors<ref name=":20" />.


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==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 fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>


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"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!Diagnostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Prognostic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Therapeutic Significance (Yes, No or Unknown)
!Clinical Relevance Details/Other Notes
!Notes
|-
|-
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
7
7
|EXAMPLE Loss
|<span class="blue-text">EXAMPLE:</span> Loss
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
chr7:1- 159,335,973 [hg38]
|EXAMPLE
 
chr7
chr7
|Yes
|<span class="blue-text">EXAMPLE:</span>
|Yes
Unknown
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE
|<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 reference).
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).
|-
|-
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
8
8
|EXAMPLE Gain
|<span class="blue-text">EXAMPLE:</span> Gain
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
chr8
|No
|<span class="blue-text">EXAMPLE:</span>
|No
Unknown
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE
|
 
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add reference).
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.
|-
|
|
|
|
|
|
|
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>


IVLBCL cases in the literature with available cytogenetic information have invariably complex karyotypes, comprising both numerical and structural changes with a median of 10 aberrations per case <ref name=":13" /><ref name=":15" /><ref name=":12" />. The most commonly detected cytogenetic abnormalities are 6q deletions, rearrangements of 8p, chromosome 1 aberrations and deletions or duplication of chromosome 18<ref name=":12">{{Cite journal|last=Deisch|first=Jeremy|last2=Fuda|first2=Franklin“Buddy”|last3=Chen|first3=Weina|last4=Karandikar|first4=Nitin|last5=Arbini|first5=Arnaldo A.|last6=Zhou|first6=Xin J.|last7=Wang|first7=Huan-You|date=2009-09-01|title=Segmental Tandem Triplication of the <i>MLL</i> Gene in an Intravascular Large B-Cell Lymphoma With Multisystem Involvement: A Comprehensive Morphologic, Immunophenotypic, Cytogenetic, and Molecular Cytogenetic Antemortem Study|url=http://dx.doi.org/10.5858/133.9.1477|journal=Archives of Pathology &amp; Laboratory Medicine|volume=133|issue=9|pages=1477–1482|doi=10.5858/133.9.1477|issn=1543-2165}}</ref><ref name=":13" /><ref name=":8" />. Recurrent cytogenetic abnormalities involving chromosomes 1, 6q and 18 occur in more than 50% of cases<ref name=":15" /> .The majority of chromosome 6 deletions involve the long arm, in particular 6q21-q23<ref name=":13" /><ref name=":15" />, a region which has been implicated in a number of other mature B-cell neoplasms, including diffuse large b-cell lymphoma(DLBCL)<ref>{{Cite journal|last=Thelander|first=Emma Flordal|last2=Ichimura|first2=Koichi|last3=Corcoran|first3=Martin|last4=Barbany|first4=Gisela|last5=Nordgren|first5=Ann|last6=Heyman|first6=Mats|last7=Berglund|first7=Mattias|last8=Mungall|first8=Andy|last9=Rosenquist|first9=Richard|date=2008-01|title=Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia|url=http://www.tandfonline.com/doi/full/10.1080/10428190701817282|journal=Leukemia & Lymphoma|language=en|volume=49|issue=3|pages=477–487|doi=10.1080/10428190701817282|issn=1042-8194}}</ref>.  Gains of chromosome 18 are common in DLBCL, mantle zone lymphoma and follicular lymphoma and, frequently, the amplified region involves the BCL2 oncogene at 18q21.3<ref name=":13" />. Whether 18q gain is associated with BCL2 protein overexpression in IVLBCL requires further analysis. Furthermore, loss of chromosome 18 has been shown to be associated with inactivation of the DCC tumour suppressor gene, located at 18q21<ref>{{Cite journal|last=Porfiri|first=E|last2=Secker-Walker|first2=LM|last3=Hoffbrand|first3=AV|last4=Hancock|first4=JF|date=1993-05-15|title=DCC tumor suppressor gene is inactivated in hematologic malignancies showing monosomy 18|url=http://dx.doi.org/10.1182/blood.v81.10.2696.bloodjournal81102696|journal=Blood|volume=81|issue=10|pages=2696–2701|doi=10.1182/blood.v81.10.2696.bloodjournal81102696|issn=0006-4971}}</ref>. One of the most frequently involved chromosome 1 loci, 1p13, contains the NOTCH2 gene<ref name=":15" />, a gene essential for the transition of B-cells towards marginal zone maturation<ref>{{Cite journal|last=Arruga|first=Francesca|last2=Vaisitti|first2=Tiziana|last3=Deaglio|first3=Silvia|date=2018|title=The NOTCH Pathway and Its Mutations in Mature B Cell Malignancies|url=https://pubmed.ncbi.nlm.nih.gov/30534535|journal=Frontiers in Oncology|volume=8|pages=550|doi=10.3389/fonc.2018.00550|issn=2234-943X|pmc=6275466|pmid=30534535}}</ref>, mutations in which have been implicated in a number of mature B-cell lymphomas.  
IVLBCL cases in the literature with available cytogenetic information have invariably complex karyotypes, comprising both numerical and structural changes with a median of 10 aberrations per case <ref name=":13" /><ref name=":15" /><ref name=":12" />. The most commonly detected cytogenetic abnormalities are 6q deletions, rearrangements of 8p, chromosome 1 aberrations and deletions or duplication of chromosome 18<ref name=":12">{{Cite journal|last=Deisch|first=Jeremy|last2=Fuda|first2=Franklin“Buddy”|last3=Chen|first3=Weina|last4=Karandikar|first4=Nitin|last5=Arbini|first5=Arnaldo A.|last6=Zhou|first6=Xin J.|last7=Wang|first7=Huan-You|date=2009-09-01|title=Segmental Tandem Triplication of the <i>MLL</i> Gene in an Intravascular Large B-Cell Lymphoma With Multisystem Involvement: A Comprehensive Morphologic, Immunophenotypic, Cytogenetic, and Molecular Cytogenetic Antemortem Study|url=http://dx.doi.org/10.5858/133.9.1477|journal=Archives of Pathology &amp; Laboratory Medicine|volume=133|issue=9|pages=1477–1482|doi=10.5858/133.9.1477|issn=1543-2165}}</ref><ref name=":13" /><ref name=":8">{{Cite journal|last=Murase|first=Takuhei|last2=Yamaguchi|first2=Motoko|last3=Suzuki|first3=Ritsuro|last4=Okamoto|first4=Masataka|last5=Sato|first5=Yumiko|last6=Tamaru|first6=Jun-ichi|last7=Kojima|first7=Masaru|last8=Miura|first8=Ikuo|last9=Mori|first9=Naoyoshi|date=2007-01-15|title=Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5|url=https://ashpublications.org/blood/article/109/2/478/23520/Intravascular-large-Bcell-lymphoma-IVLBCL-a|journal=Blood|language=en|volume=109|issue=2|pages=478–485|doi=10.1182/blood-2006-01-021253|issn=0006-4971}}</ref>. Recurrent cytogenetic abnormalities involving chromosomes 1, 6q and 18 occur in more than 50% of cases<ref name=":15" /> .The majority of chromosome 6 deletions involve the long arm, in particular 6q21-q23<ref name=":13" /><ref name=":15" />, a region which has been implicated in a number of other mature B-cell neoplasms, including diffuse large b-cell lymphoma(DLBCL)<ref>{{Cite journal|last=Thelander|first=Emma Flordal|last2=Ichimura|first2=Koichi|last3=Corcoran|first3=Martin|last4=Barbany|first4=Gisela|last5=Nordgren|first5=Ann|last6=Heyman|first6=Mats|last7=Berglund|first7=Mattias|last8=Mungall|first8=Andy|last9=Rosenquist|first9=Richard|date=2008-01|title=Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia|url=http://www.tandfonline.com/doi/full/10.1080/10428190701817282|journal=Leukemia & Lymphoma|language=en|volume=49|issue=3|pages=477–487|doi=10.1080/10428190701817282|issn=1042-8194}}</ref>.  Gains of chromosome 18 are common in DLBCL, mantle zone lymphoma and follicular lymphoma and, frequently, the amplified region involves the BCL2 oncogene at 18q21.3<ref name=":13" />. Whether 18q gain is associated with BCL2 protein overexpression in IVLBCL requires further analysis. Furthermore, loss of chromosome 18 has been shown to be associated with inactivation of the DCC tumour suppressor gene, located at 18q21<ref>{{Cite journal|last=Porfiri|first=E|last2=Secker-Walker|first2=LM|last3=Hoffbrand|first3=AV|last4=Hancock|first4=JF|date=1993-05-15|title=DCC tumor suppressor gene is inactivated in hematologic malignancies showing monosomy 18|url=http://dx.doi.org/10.1182/blood.v81.10.2696.bloodjournal81102696|journal=Blood|volume=81|issue=10|pages=2696–2701|doi=10.1182/blood.v81.10.2696.bloodjournal81102696|issn=0006-4971}}</ref>. One of the most frequently involved chromosome 1 loci, 1p13, contains the NOTCH2 gene<ref name=":15" />, a gene essential for the transition of B-cells towards marginal zone maturation<ref>{{Cite journal|last=Arruga|first=Francesca|last2=Vaisitti|first2=Tiziana|last3=Deaglio|first3=Silvia|date=2018|title=The NOTCH Pathway and Its Mutations in Mature B Cell Malignancies|url=https://pubmed.ncbi.nlm.nih.gov/30534535|journal=Frontiers in Oncology|volume=8|pages=550|doi=10.3389/fonc.2018.00550|issn=2234-943X|pmc=6275466|pmid=30534535}}</ref>, mutations in which have been implicated in a number of mature B-cell lymphomas.  


Structural variations or copy-number gains in the PD-L1 and PD-L2 encoding genes (CD274 and PDCD1LG2) occur in up to 48% of cases, primarily involving truncation of the 3'UTR sequence which leads to increased expression of PD-L1 transcripts, facilitating immune invasion<ref name=":2" />.Small series have confirmed an association between PD-L1 overexpression on IHC and tumours with 9p mutations including amplifications and structural variations<ref name=":2" />. Deish et al<ref name=":12" /> postulated that amplification of the MLL or KMTD2 gene, seen in AML and myelodysplastic disorders, may also be a recurrent abnormality in IVLBCL, based on a case they identified with tandem triplication of 11q21-23 leading to three copies of the gene, and three other reported cases in the literature, one with a segmental 11q23 duplication<ref name=":10" /> and two with a gain of chromosome 11<ref>{{Cite journal|last=Molina|first=Arturo|last2=Lombard|first2=Charles|last3=Donlon|first3=Timothy|last4=Bangs|first4=Charles D.|last5=Dorfman|first5=Ronald F.|date=1990-08-01|title=Immunohistochemical and cytogenetic studies indicate that malignant angioendotheliomatosis is a primary intravascular (angiotropic) lymphoma|url=http://dx.doi.org/10.1002/1097-0142(19900801)66:3<474::aid-cncr2820660313>3.0.co;2-p|journal=Cancer|volume=66|issue=3|pages=474–479|doi=10.1002/1097-0142(19900801)66:3<474::aid-cncr2820660313>3.0.co;2-p|issn=0008-543X}}</ref><ref name=":10" />.  
Structural variations or copy-number gains in the PD-L1 and PD-L2 encoding genes (CD274 and PDCD1LG2) occur in up to 48% of cases, primarily involving truncation of the 3'UTR sequence which leads to increased expression of PD-L1 transcripts, facilitating immune invasion<ref name=":2" />.Small series have confirmed an association between PD-L1 overexpression on IHC and tumours with 9p mutations including amplifications and structural variations<ref name=":2" />. Deish et al<ref name=":12" /> postulated that amplification of the MLL or KMTD2 gene, seen in AML and myelodysplastic disorders, may also be a recurrent abnormality in IVLBCL, based on a case they identified with tandem triplication of 11q21-23 leading to three copies of the gene, and three other reported cases in the literature, one with a segmental 11q23 duplication<ref name=":10" /> and two with a gain of chromosome 11<ref>{{Cite journal|last=Molina|first=Arturo|last2=Lombard|first2=Charles|last3=Donlon|first3=Timothy|last4=Bangs|first4=Charles D.|last5=Dorfman|first5=Ronald F.|date=1990-08-01|title=Immunohistochemical and cytogenetic studies indicate that malignant angioendotheliomatosis is a primary intravascular (angiotropic) lymphoma|url=http://dx.doi.org/10.1002/1097-0142(19900801)66:3<474::aid-cncr2820660313>3.0.co;2-p|journal=Cancer|volume=66|issue=3|pages=474–479|doi=10.1002/1097-0142(19900801)66:3<474::aid-cncr2820660313>3.0.co;2-p|issn=0008-543X}}</ref><ref name=":10" />.  
Line 247: Line 234:
|}
|}
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Characteristic Chromosomal Patterns==
==Characteristic Chromosomal or Other Global Mutational 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'')</span>


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
|-
|-
|EXAMPLE
|<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
|EXAMPLE:
|
 
|
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|-
|<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)==
==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 and common as well either disease defining and/or clinically significant. Can include references 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.'') </span>


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"
{| 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!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!'''Diagnostic Significance (Yes, No or Unknown)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span>''EGFR''


EXAMPLE:
<br />
 
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
EGFR; Exon 20 mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
 
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
EXAMPLE: BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> T
|EXAMPLE: TSG
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|EXAMPLE: 20% (COSMIC)
|<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).
 
|-
EXAMPLE: 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|EXAMPLE: IDH1 R123H
<br />
|EXAMPLE: EGFR amplification
|<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
|
|
|-
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|
|
|
|
|
|
|
|
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|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
|}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.
<br />
|}
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.
 


<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>


Due to the rarity of IVLBCL, only small series describing recurrent gene mutations are currently available. However, several studies have identified recurrent mutations in multiple genes with known aberrations in both nodal DLBCL and other extranodal lymphomas. These include driver mutations in genes involved in the B-cell receptor/NF-κβ signalling pathways (CD79B, MYD88, IRF4, ITPKB, NFKBIE and TNFAIP3), genes targeted by Activation Induced Deaminase (PIM1 and IGLL5), genes affecting B-cell development (PRDM1 and TOX) and histone modification factors (SETD1B, KMT2D and EP300)<ref name=":2" />. Although the mutational landscape of IVLBCL tends to be similar to that of ABC type nodal DLBCL, there is a higher frequency of mutations in several genes including MYD88, CD79B, TBL1XR1 and SETD1B<ref name=":2" />.   
Due to the rarity of IVLBCL, only small series describing recurrent gene mutations are currently available. However, several studies have identified recurrent mutations in multiple genes with known aberrations in both nodal DLBCL and other extranodal lymphomas. These include driver mutations in genes involved in the B-cell receptor/NF-κβ signalling pathways (CD79B, MYD88, IRF4, ITPKB, NFKBIE and TNFAIP3), genes targeted by Activation Induced Deaminase (PIM1 and IGLL5), genes affecting B-cell development (PRDM1 and TOX) and histone modification factors (SETD1B, KMT2D and EP300)<ref name=":2" />. Although the mutational landscape of IVLBCL tends to be similar to that of ABC type nodal DLBCL, there is a higher frequency of mutations in several genes including MYD88, CD79B, TBL1XR1 and SETD1B<ref name=":2" />.   


Collated, comprehensive gene mutation prevalence data is not currently available, however the table below summarises the most common gene mutations identified from a number of recent studies<ref name=":17" /><ref>{{Cite journal|last=Zhang|first=D. D.|last2=Zhang|first2=L.|last3=Zhou|first3=J.|last4=Jiang|first4=G. Z.|last5=Li|first5=P.|last6=Zhang|first6=Y. P.|last7=Wang|first7=G. N.|last8=Zhao|first8=W. G.|last9=Li|first9=W. C.|date=2021-03-08|title=[Clinicopathological features and MYD88 L265P mutation status of intravascular large B cell lymphoma]|url=https://pubmed.ncbi.nlm.nih.gov/33677885|journal=Zhonghua Bing Li Xue Za Zhi = Chinese Journal of Pathology|volume=50|issue=3|pages=217–221|doi=10.3760/cma.j.cn112151-20200513-00383|issn=0529-5807|pmid=33677885}}</ref><ref name=":2" /><ref name=":6" />:  
Collated, comprehensive gene mutation prevalence data is not currently available, however the table below summarises the most common gene mutations identified from a number of recent studies<ref name=":17" /><ref>{{Cite journal|last=Zhang|first=D. D.|last2=Zhang|first2=L.|last3=Zhou|first3=J.|last4=Jiang|first4=G. Z.|last5=Li|first5=P.|last6=Zhang|first6=Y. P.|last7=Wang|first7=G. N.|last8=Zhao|first8=W. G.|last9=Li|first9=W. C.|date=2021-03-08|title=[Clinicopathological features and MYD88 L265P mutation status of intravascular large B cell lymphoma]|url=https://pubmed.ncbi.nlm.nih.gov/33677885|journal=Zhonghua Bing Li Xue Za Zhi = Chinese Journal of Pathology|volume=50|issue=3|pages=217–221|doi=10.3760/cma.j.cn112151-20200513-00383|issn=0529-5807|pmid=33677885}}</ref><ref name=":2" /><ref name=":6">{{Cite journal|last=Suehara|first=Yasuhito|last2=Sakata-Yanagimoto|first2=Mamiko|last3=Hattori|first3=Keiichiro|last4=Nanmoku|first4=Toru|last5=Itoh|first5=Takayoshi|last6=Kaji|first6=Daisuke|last7=Yamamoto|first7=Go|last8=Abe|first8=Yoshiaki|last9=Narita|first9=Kentaro|date=2018-06|title=Liquid biopsy for the identification of intravascular large B-cell lymphoma|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2017.178830|journal=Haematologica|language=en|volume=103|issue=6|pages=e241–e244|doi=10.3324/haematol.2017.178830|issn=0390-6078|pmc=PMC6058794|pmid=29472348}}</ref>:  


{| class="wikitable sortable"
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<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==
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==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|EXAMPLE: MAPK signaling
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|EXAMPLE: Increased cell growth and proliferation
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|EXAMPLE: Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|EXAMPLE: Unregulated cell division
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|EXAMPLE:  Abnormal gene expression program
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|-
|
|
|
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>


One of the most widely studied genes in IVLBCL is MYD88 with 45% of patients found to have a somatic MYD88 mutation, 86% of these being L265P mutations. This mutation is commonly associated with lymphoplasmacytic lymphoma and  Waldenstrom macroglobulinaemia (WM), being present in >90% of WM cases and 54% of IgM MGUS patients<ref>{{Cite journal|last=Xu|first=Lian|last2=Hunter|first2=Zachary R.|last3=Yang|first3=Guang|last4=Zhou|first4=Yangsheng|last5=Cao|first5=Yang|last6=Liu|first6=Xia|last7=Morra|first7=Enrica|last8=Trojani|first8=Alessandra|last9=Greco|first9=Antonino|date=2013-03-14|title=MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction|url=https://ashpublications.org/blood/article/121/11/2051/31090/MYD88-L265P-in-Waldenstr%C3%B6m-macroglobulinemia|journal=Blood|language=en|volume=121|issue=11|pages=2051–2058|doi=10.1182/blood-2012-09-454355|issn=0006-4971|pmc=PMC3596964|pmid=23321251}}</ref>. MYD L265P mutations have also been found in 29% of activated B-cell (ABC) type DLBCL<ref name=":20">{{Cite journal|last=Ngo|first=Vu N.|last2=Young|first2=Ryan M.|last3=Schmitz|first3=Roland|last4=Jhavar|first4=Sameer|last5=Xiao|first5=Wenming|last6=Lim|first6=Kian-Huat|last7=Kohlhammer|first7=Holger|last8=Xu|first8=Weihong|last9=Yang|first9=Yandan|date=2011-02|title=Oncogenically active MYD88 mutations in human lymphoma|url=http://www.nature.com/articles/nature09671|journal=Nature|language=en|volume=470|issue=7332|pages=115–119|doi=10.1038/nature09671|issn=0028-0836|pmc=PMC5024568|pmid=21179087}}</ref>, and can be seen in primary cutaneous DLBCL, testicular and primary CNS DLBCL and DLBCL of leg type<ref>Swerdlow SH, et al,, (2017). Lymphoplasmacytic lymphoma, in World Health Organisation Classificaiton of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4<sup>th</sup> edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p330-334.</ref>. Overall, the mutational profile of IVLBCL is more similar to these entities than to DLBCL, NOS<ref name=":2" />. Ngo et al<ref name=":20" /> demonstrated that in ABC-type DLBCL L265P functions as a gain-of-function driver mutation which promotes cell survival through the promotion of NF-κβ and JAK-STAT3 signalling. Given that IVLBCL is overwhelmingly of ABC type, the role of MYD L265P as a driver mutation in IVLBCL should be considered. Some studies have also shown that TNFAIP3 loss (observed in approximately 24% of IVLBCL) acts synergistically with MYD88 L265P to drive upregulation of anti-apoptotic signalling in DLBCL<ref name=":21">{{Cite journal|last=Wenzl|first=Kerstin|last2=Manske|first2=Michelle K.|last3=Sarangi|first3=Vivekananda|last4=Asmann|first4=Yan W.|last5=Greipp|first5=Patricia T.|last6=Schoon|first6=Hanna R.|last7=Braggio|first7=Esteban|last8=Maurer|first8=Matthew J.|last9=Feldman|first9=Andrew L.|date=2018-10-09|title=Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/30301877|journal=Blood Cancer Journal|volume=8|issue=10|pages=97|doi=10.1038/s41408-018-0130-3|issn=2044-5385|pmc=6177394|pmid=30301877}}</ref>. Loss of TNFAIP3 occurs in around 55% of DLBCL and also contributes to higher baseline phosphorylation of NF-κβ and STAT3 as well as p38 which, in association with NF-κβ, causes upregulation of BCL2 and MYC<ref name=":21" />. IGLL5 located at 22q11, which is mutated in around 90% of IVLBCL, is a recurrently mutated gene in DLBCL and multiple myeloma, in which mutations confer an increased risk of disease progression<ref>{{Cite journal|last=White|first=Brian S.|last2=Lanc|first2=Irena|last3=O'Neal|first3=Julie|last4=Gupta|first4=Harshath|last5=Fulton|first5=Robert S.|last6=Schmidt|first6=Heather|last7=Fronick|first7=Catrina|last8=Belter|first8=Edward A.|last9=Fiala|first9=Mark|date=2018-03-21|title=A multiple myeloma-specific capture sequencing platform discovers novel translocations and frequent, risk-associated point mutations in IGLL5|url=https://pubmed.ncbi.nlm.nih.gov/29563506|journal=Blood Cancer Journal|volume=8|issue=3|pages=35|doi=10.1038/s41408-018-0062-y|issn=2044-5385|pmc=5862875|pmid=29563506}}</ref>.   
One of the most widely studied genes in IVLBCL is MYD88 with 45% of patients found to have a somatic MYD88 mutation, 86% of these being L265P mutations. This mutation is commonly associated with lymphoplasmacytic lymphoma and  Waldenstrom macroglobulinaemia (WM), being present in >90% of WM cases and 54% of IgM MGUS patients<ref>{{Cite journal|last=Xu|first=Lian|last2=Hunter|first2=Zachary R.|last3=Yang|first3=Guang|last4=Zhou|first4=Yangsheng|last5=Cao|first5=Yang|last6=Liu|first6=Xia|last7=Morra|first7=Enrica|last8=Trojani|first8=Alessandra|last9=Greco|first9=Antonino|date=2013-03-14|title=MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction|url=https://ashpublications.org/blood/article/121/11/2051/31090/MYD88-L265P-in-Waldenstr%C3%B6m-macroglobulinemia|journal=Blood|language=en|volume=121|issue=11|pages=2051–2058|doi=10.1182/blood-2012-09-454355|issn=0006-4971|pmc=PMC3596964|pmid=23321251}}</ref>. MYD L265P mutations have also been found in 29% of activated B-cell (ABC) type DLBCL<ref name=":20">{{Cite journal|last=Ngo|first=Vu N.|last2=Young|first2=Ryan M.|last3=Schmitz|first3=Roland|last4=Jhavar|first4=Sameer|last5=Xiao|first5=Wenming|last6=Lim|first6=Kian-Huat|last7=Kohlhammer|first7=Holger|last8=Xu|first8=Weihong|last9=Yang|first9=Yandan|date=2011-02|title=Oncogenically active MYD88 mutations in human lymphoma|url=http://www.nature.com/articles/nature09671|journal=Nature|language=en|volume=470|issue=7332|pages=115–119|doi=10.1038/nature09671|issn=0028-0836|pmc=PMC5024568|pmid=21179087}}</ref>, and can be seen in primary cutaneous DLBCL, testicular and primary CNS DLBCL and DLBCL of leg type<ref>Swerdlow SH, et al,, (2017). Lymphoplasmacytic lymphoma, in World Health Organisation Classificaiton of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4<sup>th</sup> edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p330-334.</ref>. Overall, the mutational profile of IVLBCL is more similar to these entities than to DLBCL, NOS<ref name=":2" />. Ngo et al<ref name=":20" /> demonstrated that in ABC-type DLBCL L265P functions as a gain-of-function driver mutation which promotes cell survival through the promotion of NF-κβ and JAK-STAT3 signalling. Given that IVLBCL is overwhelmingly of ABC type, the role of MYD L265P as a driver mutation in IVLBCL should be considered. Some studies have also shown that TNFAIP3 loss (observed in approximately 24% of IVLBCL) acts synergistically with MYD88 L265P to drive upregulation of anti-apoptotic signalling in DLBCL<ref name=":21">{{Cite journal|last=Wenzl|first=Kerstin|last2=Manske|first2=Michelle K.|last3=Sarangi|first3=Vivekananda|last4=Asmann|first4=Yan W.|last5=Greipp|first5=Patricia T.|last6=Schoon|first6=Hanna R.|last7=Braggio|first7=Esteban|last8=Maurer|first8=Matthew J.|last9=Feldman|first9=Andrew L.|date=2018-10-09|title=Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/30301877|journal=Blood Cancer Journal|volume=8|issue=10|pages=97|doi=10.1038/s41408-018-0130-3|issn=2044-5385|pmc=6177394|pmid=30301877}}</ref>. Loss of TNFAIP3 occurs in around 55% of DLBCL and also contributes to higher baseline phosphorylation of NF-κβ and STAT3 as well as p38 which, in association with NF-κβ, causes upregulation of BCL2 and MYC<ref name=":21" />. IGLL5 located at 22q11, which is mutated in around 90% of IVLBCL, is a recurrently mutated gene in DLBCL and multiple myeloma, in which mutations confer an increased risk of disease progression<ref>{{Cite journal|last=White|first=Brian S.|last2=Lanc|first2=Irena|last3=O'Neal|first3=Julie|last4=Gupta|first4=Harshath|last5=Fulton|first5=Robert S.|last6=Schmidt|first6=Heather|last7=Fronick|first7=Catrina|last8=Belter|first8=Edward A.|last9=Fiala|first9=Mark|date=2018-03-21|title=A multiple myeloma-specific capture sequencing platform discovers novel translocations and frequent, risk-associated point mutations in IGLL5|url=https://pubmed.ncbi.nlm.nih.gov/29563506|journal=Blood Cancer Journal|volume=8|issue=3|pages=35|doi=10.1038/s41408-018-0062-y|issn=2044-5385|pmc=5862875|pmid=29563506}}</ref>.   


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
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==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: Once you have a text placeholder entered to which you want to add a link, highlight that text, 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 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==
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(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />


'''
<br />


==Notes==
==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>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 [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
 
Prior Author(s): 
 
       
<nowiki>*</nowiki>''Citation of this Page'': “Intravascular large B-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Intravascular_large_B-cell_lymphoma</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Intravascular large B-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Intravascular_large_B-cell_lymphoma</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases I]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases I]]
Retrieved from "https://test.ccga.io/index.php/HAEM5:Intravascular_large_B-cell_lymphoma"