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

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" />.  

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" />.

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==Sites of Involvement==

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.

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

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" />.

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==Individual Region Genomic Gain / Loss / LOH==

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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.  

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==Characteristic Chromosomal Patterns==

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" />.   

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==Epigenomic Alterations==

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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^th 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>.   

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==Genetic Diagnostic Testing Methods==