View source for HAEM4:Intravascular Large B-cell Lymphoma

{{DISPLAYTITLE:Intravascular Large B-cell Lymphoma}}


<blockquote class='blockedit'>{{Box-round|title=PREVIOUS EDITION|This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition [[HAEM5:Table_of_Contents|Table of Contents]].
}}</blockquote>
==Primary Author(s)*==

Kate Berry, MBBS, BBus (Hons), Pathology Queensland

__TOC__

==Cancer Category/Type==

Mature B-cell neoplasms

==Cancer Sub-Classification / Subtype==

Intravascular large B-cell lymphoma

==Definition / Description of Disease==

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>

==Synonyms / 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==

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" />.

==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. 

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||CD20, CD79a
|-
|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" />
|-
|Negative (universal)||EBER-ISH, Cyclin D1, CD30
|-
|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" />
|}

==Chromosomal Rearrangements (Gene Fusions)==

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.
==Genomic Gain/Loss/LOH==

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. 

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" />. 

{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|1<ref name=":13" />
|Loss
|whole chromosome
|-
|3<ref name=":13" /><ref name=":11" />||Loss||q21-qter
|-
|6<ref name=":2" /><ref name=":13" />||Loss||q21-q23; q11-qter
|-
|8<ref name=":13" />
|Loss
|p21-qter
|-
|9<ref name=":13" />
|Loss
|p21-pter; p22-qter
|-
|15<ref name=":13" />
|Loss
|whole chromosome
|-
|18<ref name=":13" /><ref name=":2" />
|Gain
|whole chromosome, 11q13→qter region
|-
|18<ref name=":13" />
|Loss
|q23
|-
|21
|Amp
|q
|-
|22<ref name=":13" />
|Loss
|q21-q23
|}	
		
==Gene Mutations (SNV/INDEL)==

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" />: 

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|IGLL5|| ||Not fully characterised|| ||90% (19/21)
|-
|PIM1
|
|Oncogene
|GOF
|83% (25/30)
|-
|SET1B
|
|Not fully characterised
|
|57% (12/21)
|-
|CD79B
|
|Oncogene
|GOF; Driver
|49% (26/53)
|-
|MYD88
|L265P
|Oncogene
|GOF; Driver
|45% (29/65)
|-
|PRDM1
|
|Tumour suppressor
|LOF
|43% (13/30)
|-
|IRF4
|
|Oncogene
|GOF
|38% (8/21)
|-
|TOX3
|
|Not fully characterised
|
|33% (7/21)
|-
|TNFAIP3
|
|Tumour suppressor
|LOF
|24% (5/21)
|-
|KMT2D
|
|Tumour suppressor
|LOF
|24% (5/21)
|-
|BTG2
|
|Tumour suppressor
|LOF
|22% (2/9)
|-
|ITPKB
|
|Tumour suppressor
|LOF
|14% (3/21)
|-
|NFKBIE
|
|Tumour suppressor
|LOF
|14% (3/21)
|-
|EP300
|
|Oncogene
|GOF
|14% (3/21)
|}	
		
==Epigenomics (Methylation)==

Although the role of epigenomics in IVLBCL specifically has been incompletely described, several of the genes most frequently mutated in IVLBCL have been shown to be epigenetic determinants in DLBCL, including KMT2D and EP300.

KMT2D mutants promote lymphomagenesis in part by impeding H3K4 methylation, driving enhanced proliferation in germinal centres, and impeding terminal differentiation of B-cells<ref name=":18">{{Cite journal|last=Ortega-Molina|first=Ana|last2=Boss|first2=Isaac W.|last3=Canela|first3=Andres|last4=Pan|first4=Heng|last5=Jiang|first5=Yanwen|last6=Zhao|first6=Chunying|last7=Jiang|first7=Man|last8=Hu|first8=Deqing|last9=Agirre|first9=Xabier|date=2015-10|title=The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676270/|journal=Nature medicine|volume=21|issue=10|pages=1199–1208|doi=10.1038/nm.3943|issn=1078-8956|pmc=4676270|pmid=26366710}}</ref>. The extent to which KMT2D inactivation promotes lymphomagenesis appears to be affected by dysregulation of the expression of a number of other genes, including BCL2 and AICDA. KMT2D loss, in combination with increased BCL2 expression, has been shown in mouse models to increase lymphoma incidence from that of mice with wild type KMT2D, and the effect is greater for those with homozygous deletions<ref name=":18" /><ref>{{Cite journal|last=Zhang|first=Jiyuan|last2=Dominguez-Sola|first2=David|last3=Hussein|first3=Shafinaz|last4=Lee|first4=Ji-Eun|last5=Holmes|first5=Antony B|last6=Bansal|first6=Mukesh|last7=Vlasevska|first7=Sofija|last8=Mo|first8=Tongwei|last9=Tang|first9=Hongyan|date=2015-10|title=Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis|url=http://www.nature.com/articles/nm.3940|journal=Nature Medicine|language=en|volume=21|issue=10|pages=1190–1198|doi=10.1038/nm.3940|issn=1078-8956|pmc=PMC5145002|pmid=26366712}}</ref>. AICDA encodes activation-induced cytidine deaminase (AID), an enzyme involved in somatic hypermutation, class switch recombination and gene conversion in the process of immunoglobulin diversification. Overexpression of AICDA  has been shown in mice models, in combination with KMT2D inactivation, to be associated with increased lymphoma incidence and also with more aggressive phenotypes than tumours with KMT2D deletion alone<ref name=":18" />.

In DLBCL, mutations in EP300, a histone acetyltransferase, have been shown to inhibit H3K27 acetylation and activate the NOTCH signalling pathway, possibly through inhibition of FBXW7 expression, which acts as a NOTCH suppressor<ref name=":19">{{Cite journal|last=Huang|first=Yao-Hui|last2=Cai|first2=Kun|last3=Xu|first3=Peng-Peng|last4=Wang|first4=Li|last5=Huang|first5=Chuan-Xin|last6=Fang|first6=Ying|last7=Cheng|first7=Shu|last8=Sun|first8=Xiao-Jian|last9=Liu|first9=Feng|date=2021-12|title=CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis|url=http://www.nature.com/articles/s41392-020-00437-8|journal=Signal Transduction and Targeted Therapy|language=en|volume=6|issue=1|pages=10|doi=10.1038/s41392-020-00437-8|issn=2059-3635|pmc=PMC7801454|pmid=33431788}}</ref>. The NOTCH pathway plays a critical role in normal B-cell development and dysregulation of NOTCH signalling has been implicated in a wide array of mature B-cell malignancies, including DLBCL<ref>{{Cite journal|last=Arruga|first=Francesca|last2=Vaisitti|first2=Tiziana|last3=Deaglio|first3=Silvia|date=2018-11-26|title=The NOTCH Pathway and Its Mutations in Mature B Cell Malignancies|url=https://www.frontiersin.org/article/10.3389/fonc.2018.00550/full|journal=Frontiers in Oncology|volume=8|pages=550|doi=10.3389/fonc.2018.00550|issn=2234-943X|pmc=PMC6275466|pmid=30534535}}</ref>. Additionally, mutations in EP300 have been shown to promote tumour-associated macrophage (TAM) activation, as evidenced by increased macrophages in the tumour microenvironment, which promote tumour progression by inhibiting T-cell immunity<ref name=":19" />. Notably, patients with mutations in EP300 and CREBBP, a closely related chromatin-modifying gene, have been shown to have significantly lower 3-year progression-free and overall survival rates than patients with wild-type EP300/CREBBP<ref name=":19" />

==Genes and Main Pathways Involved==

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>.  

==Diagnostic Testing Methods==

Due to its non-specific clinical presentation and frequent lack of characteristic radiological findings, such as lymphadenopathy, IVLBCL often poses a diagnostic challenge. When IVLBCL is suspected clinically, random skin biopsy is easy to perform and frequently diagnostic<ref name=":6" />, with tumour cells often observed in subcutaneous tissues, even in the absence of macroscopic lesions<ref name=":5">{{Cite journal|last=Matsue|first=Kosei|last2=Asada|first2=Noboru|last3=Odawara|first3=Jun|last4=Aoki|first4=Takayoshi|last5=Kimura|first5=Shun-ichi|last6=Iwama|first6=Kan-ichi|last7=Fujiwara|first7=Hideaki|last8=Yamakura|first8=Masayuki|last9=Takeuchi|first9=Masami|date=2011-04|title=Random skin biopsy and bone marrow biopsy for diagnosis of intravascular large B cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/20957365|journal=Annals of Hematology|volume=90|issue=4|pages=417–421|doi=10.1007/s00277-010-1101-3|issn=1432-0584|pmid=20957365}}</ref>. However, as the lymphoma cells are most commonly found within the subcutaneous adipose tissues, rather than the dermis, inadequate hypodermic sampling may lead to false negative results<ref name=":4" />. Although intrasinusoidal infiltration of the bone marrow is considered to be characteristic of IVLBCL, nodular and interstitial infiltration are often also seen, making it difficult on bone marrow biopsy alone to distinguish it from splenic and primary bone marrow DLBCL which show many common clinical features and immunohistochemical findings<ref name=":4" />. 

The use of plasma- and serum-derived cell-free DNA (cfDNA) is emerging as a potential non-invasive means of obtaining tumour material for both diagnosis and genetic testing. A 2021 study by Shimada et al<ref name=":2" /> showed the yield of cfDNA to be ten times higher in patients with IVLBCL than diffuse large B-cell lymphoma, and significantly higher than that from healthy controls. Furthermore, cfDNA levels were significantly correlated with serum lactate dehydrogenase level and the status of bone marrow invasion, and rapidly decreased after commencing chemotherapy, whilst being elevated in the refractory phase. This not only suggests that cfDNA is mainly derived from lymphoma cells, but that lactate dehydrogenase level is a reliable surrogate marker for monitoring disease progression and response to treatment. When using whole-exome sequencing to compare mutations detected in plasma-derived cf-DNA to those in bone marrow samples, not only did the mutations observed in cf-DNA have substantially higher variant allele frequencies (a marker of intratumoural heterogeneity),  suggesting that tumour-derived DNA is significantly enriched in cfDNA, but many mutations detected in cfDNA were not found in the corresponding bone marrow samples, suggesting improved sensitivity with the use of cf-DNA over bone marrow samples<ref name=":2" />. Variant allele frequency has also been shown to be significantly higher in cfDNA than tissue-derived DNA samples, with increased sensitivity<ref name=":6" />. In patients with an L265P MYD88 mutation, monitoring of cfDNA has been shown in small-scale longitudinal analysis to be of potential diagnostic utility, with detectable L265P MYD88 in cfDNA from one patient 117 days prior to definitive diagnosis, at a time in which bone marrow biopsy was negative, and in three patients prior to a definite diagnosis of disease relapse<ref name=":6" />.

In a study in 1997, DiGiuseppe et al.<ref>{{Cite journal|last=DiGiuseppe|first=J. A.|last2=Hartmann|first2=D. P.|last3=Freter|first3=C.|last4=Cossman|first4=J.|last5=Mann|first5=R. B.|date=1997-01|title=Molecular detection of bone marrow involvement in intravascular lymphomatosis|url=https://pubmed.ncbi.nlm.nih.gov/9021724|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=10|issue=1|pages=33–37|issn=0893-3952|pmid=9021724}}</ref> detected monoclonal B-cell populations by IgH gene rearrangement studies in the bone marrow of 5/5 cases of IVLBCL studied, all of whom had histologically non-involved marrow, suggesting both that marrow involvement may be under-recognised in IVLBCL, and that bone marrow biopsy may be a useful diagnostic tool to provide material for genetic testing, even when disease cannot be visualised histologically within the bone marrow.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

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" />.

==Familial Forms==

No known familial association exists.

==Other Information==

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==Links==

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==References==
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==Notes==
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[[Category:HAEM4]] [[Category:DISEASE]]