Bailey.Glen: Created page with "==Primary Author(s)*== Patricia V. Hernandez, M.D., Washington University School of Medicine TOC ==Cancer Category/Type== Immunodeficiency-Associated Lymphoproliferati..."

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Created page with "==Primary Author(s)*== Patricia V. Hernandez, M.D., Washington University School of Medicine __TOC__ ==Cancer Category/Type== Immunodeficiency-Associated Lymphoproliferati..."

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==Primary Author(s)*==

Patricia V. Hernandez, M.D., Washington University School of Medicine

__TOC__

==Cancer Category/Type==

Immunodeficiency-Associated Lymphoproliferative Disorders

==Cancer Sub-Classification / Subtype==

Lymphomas Associated with HIV Infection

==Definition / Description of Disease==

Lymphomas associated with HIV infection are a heterogeneous group of aggressive B-cell non-Hodgkin lymphomas that arise in individuals with active HIV infection. They are not currently assigned a separate International Classification of Diseases for Oncology Code, instead they are grouped with other morphologically or phenotypically similar hematological malignancies in the WHO guidelines. <ref name=":0">{{Cite journal|last=Yarchoan|first=Robert|last2=Uldrick|first2=Thomas S.|date=2018-03-15|title=HIV-Associated Cancers and Related Diseases|url=https://pubmed.ncbi.nlm.nih.gov/29539283|journal=The New England Journal of Medicine|volume=378|issue=11|pages=1029–1041|doi=10.1056/NEJMra1615896|issn=1533-4406|pmc=6890231|pmid=29539283}}</ref> These diseases include, but are not limited to, lymphoproliferative disorders associated with Epstein-Barr virus (EBV) infected tumor cells such as plasmablastic lymphoma and primary effusion lymphoma. <ref name=":0" /> Diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and primary central nervous system (CNS) lymphoma are stage 3 (i.e. acquired immunodeficiency syndrome (AIDS))-defining illnesses, in the context of preexisting HIV infection. <ref>{{Cite journal|last=Centers for Disease Control and Prevention (CDC)|date=2014-04-11|title=Revised surveillance case definition for HIV infection--United States, 2014|url=https://pubmed.ncbi.nlm.nih.gov/24717910|journal=MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports|volume=63|issue=RR-03|pages=1–10|issn=1545-8601|pmid=24717910}}</ref> Hodgkin lymphoma is not an AIDS-defining illness, but the incidence of Hodgkin lymphoma is significantly increased in the context of HIV infection. Lymphomas associated with HIV infection can be categorized into the following groups:

*[[Diffuse Large B-cell Lymphoma, Not Otherwise Specified|Diffuse large B-cell lymphoma (DLBCL)]]
*[[Burkitt Lymphoma|Burkitt lymphoma]]
*Primary CNS lymphoma
*Primary effusion lymphoma
*[[Plasmablastic Lymphoma|Plasmablastic lymphoma]]
*KSHV-associated multicentric Castleman disease
*[[Hodgkin Lymphomas|Hodgkin lymphoma]]

==Synonyms / Terminology==

*HIV-related lymphomas
*AIDS-related lymphomas
*HIV-associated cancers

==Epidemiology / Prevalence==

In a study involving 448,258 people living with HIV from 1996 to 2012 in the United States, 3,687 individuals presented with lymphomas associated with HIV infection, representing 17.3% of all cancers (21,294 cases) in HIV-infected population. <ref name=":1">{{Cite journal|last=Hernández-Ramírez|first=Raúl U.|last2=Shiels|first2=Meredith S.|last3=Dubrow|first3=Robert|last4=Engels|first4=Eric A.|date=2017-11|title=Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study|url=https://pubmed.ncbi.nlm.nih.gov/28803888|journal=The lancet. HIV|volume=4|issue=11|pages=e495–e504|doi=10.1016/S2352-3018(17)30125-X|issn=2352-3018|pmc=5669995|pmid=28803888}}</ref> The most common type of HIV-related lymphoma observed was DLBCL, accounting for 48% of cases, followed by Burkitt lymphoma (18%). <ref name=":5">{{Cite journal|last=Marques-Piubelli|first=Mario L.|last2=Salas|first2=Yessenia I.|last3=Pachas|first3=Carlos|last4=Becker-Hecker|first4=Renato|last5=Vega|first5=Francisco|last6=Miranda|first6=Roberto N.|date=2020-01|title=Epstein-Barr virus-associated B-cell lymphoproliferative disorders and lymphomas: a review|url=https://pubmed.ncbi.nlm.nih.gov/31706670|journal=Pathology|volume=52|issue=1|pages=40–52|doi=10.1016/j.pathol.2019.09.006|issn=1465-3931|pmid=31706670}}</ref> The incidence of Hodgkin lymphoma is 5-20 times higher in HIV-positive patients than in HIV-negative control groups. <ref name=":2">{{Cite journal|last=Meister|first=Anne|last2=Hentrich|first2=Marcus|last3=Wyen|first3=Christoph|last4=Hübel|first4=Kai|date=2018-07|title=Malignant lymphoma in the HIV-positive patient|url=https://pubmed.ncbi.nlm.nih.gov/29663523|journal=European Journal of Haematology|volume=101|issue=1|pages=119–126|doi=10.1111/ejh.13082|issn=1600-0609|pmid=29663523}}</ref> The severity of functional immunodeficiency of patients living with HIV infection, mainly assessed via the measurement of declining CD4 cell counts, is closely linked to the pathogenesis of HIV-related lymphomas. <ref name=":2" /> HIV infection may contribute to the development of malignancy via multiple mechanisms, including downregulation of cellular and viral immunosurveillance, chronic inflammatory activation, and direct genetic damage by HIV. <ref name=":5" /><ref name=":15">{{Cite journal|last=Linke-Serinsöz|first=Ebru|last2=Fend|first2=Falko|last3=Quintanilla-Martinez|first3=Leticia|date=2017-07|title=Human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) related lymphomas, pathology view point|url=https://pubmed.ncbi.nlm.nih.gov/28506687|journal=Seminars in Diagnostic Pathology|volume=34|issue=4|pages=352–363|doi=10.1053/j.semdp.2017.04.003|issn=0740-2570|pmid=28506687}}</ref>

==Clinical Features==

Lymphoproliferative disorders may be the initial presentation of an HIV infection, particularly in the case of aggressive B-cell lymphomas or Hodgkin lymphomas. <ref name=":0" /> The severity of CD4 count reductions correlates with the types of lymphoma most likely to develop, as shown in the below table.
{| class="wikitable"
|+
!Lymphoma type
!'''Signs and Symptoms'''
!'''CD4 count'''
|-
|[[Diffuse large B-cell lymphoma|DLBCL]]
|Extranodal and disseminated disease at presentation are more common in HIV-associated DLBCL. The central nervous and gastrointestinal systems are the most commonly involved extra-nodal sites. <ref>{{Cite journal|last=Grogg|first=K. L.|last2=Miller|first2=R. F.|last3=Dogan|first3=A.|date=2007-12|title=HIV infection and lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/18042692|journal=Journal of Clinical Pathology|volume=60|issue=12|pages=1365–1372|doi=10.1136/jcp.2007.051953|issn=1472-4146|pmc=2095580|pmid=18042692}}</ref>
|CD4 < 200/μL <ref name=":2" />
|-
|[[Burkitt Lymphoma|Burkitt lymphoma]]
|The initial presentation is often due to symptoms associated with tumor expansion at sites of extra-nodal involvement (e.g. GI symptoms and cytopenias), although B symptoms (i.e. fever, night sweats, and weight loss) are also common. <ref name=":3">{{Cite journal|last=Atallah-Yunes|first=Suheil Albert|last2=Murphy|first2=Dermot J.|last3=Noy|first3=Ariela|date=2020-08|title=HIV-associated Burkitt lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/32735838|journal=The Lancet. Haematology|volume=7|issue=8|pages=e594–e600|doi=10.1016/S2352-3026(20)30126-5|issn=2352-3026|pmid=32735838}}</ref>
|CD4 > 200/μL<ref name=":3" /><ref name=":2" />
|-
|AIDS-related primary CNS lymphoma
|Focal neurologic deficits, an altered level of consciousness, behavioral changes, seizures, and other symptoms related to intracranial mass effect are the main presentations. Imaging usually demonstrates enhanced single ring-enhancing CNS lesions. <ref name=":4">{{Cite journal|last=Grommes|first=Christian|last2=DeAngelis|first2=Lisa M.|date=2017-07-20|title=Primary CNS Lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/28640701|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=35|issue=21|pages=2410–2418|doi=10.1200/JCO.2017.72.7602|issn=1527-7755|pmc=5516483|pmid=28640701}}</ref>
|CD4 < 100/μL <ref name=":0" />
|-
|Primary effusion lymphoma
|Originally described as an isolated malignant effusion of serous cavities (pleural, pericardial and/or peritoneal), however nodal and extra-nodal manifestations may occur. <ref name=":0" /> Commonly seen with another HHV-8 related disease, such as Kaposi's sarcoma, KSHV-associated multicentric Castleman disease, or both. <ref name=":0" /><ref name=":2" />
|Decreased <ref>{{Cite journal|last=Shimada|first=Kazuyuki|last2=Hayakawa|first2=Fumihiko|last3=Kiyoi|first3=Hitoshi|date=2018-11-01|title=Biology and management of primary effusion lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/30154110|journal=Blood|volume=132|issue=18|pages=1879–1888|doi=10.1182/blood-2018-03-791426|issn=1528-0020|pmid=30154110}}</ref><ref>{{Cite journal|last=Chen|first=Yi-Bin|last2=Rahemtullah|first2=Aliyah|last3=Hochberg|first3=Ephraim|date=2007-05|title=Primary effusion lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/17522245|journal=The Oncologist|volume=12|issue=5|pages=569–576|doi=10.1634/theoncologist.12-5-569|issn=1083-7159|pmid=17522245}}</ref>
|-
|[[Plasmablastic Lymphoma|Plasmablastic lymphoma]]
|Involvement of oral cavity and mandibular lesions are common. However, both nodal and extra-nodal manifestations may occur. <ref name=":0" />
|CD4 < 200/μL <ref name=":2" />
|-
|KSHV-associated multicentric Castleman disease
|Fever, cachexia, sweats, lymphadenopathy, hepatosplenomegaly and hypoalbuminemia. <ref name=":0" /><ref name=":16">{{Cite journal|last=Wang|first=Hao-Wei|last2=Pittaluga|first2=Stefania|last3=Jaffe|first3=Elaine S.|date=2016-09|title=Multicentric Castleman disease: Where are we now?|url=https://pubmed.ncbi.nlm.nih.gov/27296355|journal=Seminars in Diagnostic Pathology|volume=33|issue=5|pages=294–306|doi=10.1053/j.semdp.2016.05.006|issn=0740-2570|pmc=5003700|pmid=27296355}}</ref> Can coexist with plasma cell dyscrasias and in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). <ref name=":2" /><ref name=":16" />
|No correlation with CD4 count <ref name=":2" />
|-
|[[Hodgkin Lymphomas|Hodgkin lymphoma]]
|Associated with advanced age. B symptoms are more common than in HIV-negative patients. <ref name=":0" /> Additionally, unusual presentations with extranodal symptoms may occur. <ref name=":0" />
|CD4 > 200/μL <ref name=":2" />
|}
==Sites of Involvement==

Extra-nodal involvement is common <ref name=":2" /><ref name=":15" /><ref>{{Cite journal|last=Noy|first=Ariela|date=2020 May/Jun|title=HIV Lymphoma and Burkitts Lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/32496459|journal=Cancer Journal (Sudbury, Mass.)|volume=26|issue=3|pages=260–268|doi=10.1097/PPO.0000000000000448|issn=1540-336X|pmid=32496459}}</ref>:

*CNS
*GI
*Serous body cavities
*Bone marrow
*Oral cavity/pharynx

==Morphologic Features==
Morphologic features are heterogeneous and will depend on lymphoma type:
{| class="wikitable"
!Lymphoma type
!'''Morphologic features'''
|-
|[[Diffuse large B-cell lymphoma|DLBCL]]
|B-cell neoplasm that is classified into:
- Germinal B-cell (mainly centroblastic variant): accounts for 25% of HIV-related DLBCL, being characterized by a diffuse proliferation of neoplastic cells with moderately abundant cytoplasm and round regular nuclei containing with two or more prominent nucleoli. <ref name=":8">{{Cite journal|last=Carbone|first=Antonino|date=2003-01|title=Emerging pathways in the development of AIDS-related lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/12517536|journal=The Lancet. Oncology|volume=4|issue=1|pages=22–29|doi=10.1016/s1470-2045(03)00957-4|issn=1470-2045|pmid=12517536}}</ref>

- Non-germinal B-cell (mainly represented by activated/immunoblastic and plasmablastic variant): large blastic cells with a small basophilic cytoplasm and large nuclei. It presents Ki67-index higher than 80%. <ref name=":8" />
|-
|[[Burkitt Lymphoma|Burkitt lymphoma]]
|Similar to endemic and sporadic Burkitt lymphoma; classical starry-sky appearance, with small cells with abundant basophilic cytoplasm, round nuclei with two to four nucleoli. Tumors display high mitotic activity, with Ki67-index of 95% or higher. Can display plasmacytoid differentiation. <ref name=":5" /><ref name=":3" /><ref name=":8" />
|-
|AIDS-related primary CNS lymphoma
|Primary CNS lymphomas are DLBCL in the vast majority of cases (non-germinal center B-cell subtype). Rarely, they can display a more Burkitt-like morphology. <ref name=":4" />
|-
|Primary effusion lymphoma
|Monoclonal B-cell population, with mixed characteristics of anaplastic large-cell and plasmablastic lymphomas. <ref>{{Cite journal|last=Carbone|first=Antonino|last2=Cesarman|first2=Ethel|last3=Spina|first3=Michele|last4=Gloghini|first4=Annunziata|last5=Schulz|first5=Thomas F.|date=2009-02-05|title=HIV-associated lymphomas and gamma-herpesviruses|url=https://pubmed.ncbi.nlm.nih.gov/18955561|journal=Blood|volume=113|issue=6|pages=1213–1224|doi=10.1182/blood-2008-09-180315|issn=1528-0020|pmid=18955561}}</ref> Cytoplasm is abundant and basophilic, with a large nucleus and prominent nucleoli. <ref name=":13">{{Cite journal|last=Carbone|first=Antonino|last2=Gloghini|first2=Annunziata|date=2005-09|title=AIDS-related lymphomas: from pathogenesis to pathology|url=https://pubmed.ncbi.nlm.nih.gov/16115121|journal=British Journal of Haematology|volume=130|issue=5|pages=662–670|doi=10.1111/j.1365-2141.2005.05613.x|issn=0007-1048|pmid=16115121}}</ref>
|-
|[[Plasmablastic Lymphoma|Plasmablastic lymphoma]]
|Features similar to activated B-cell DLBCL, a starry-sky pattern and/or high mitotic activity with Ki67-index > 80% may be seen. Malignant cells may be distinctive large plasmablasts with abundant basophilic cytoplasm and large nuclei. <ref name=":5" /><ref name=":13" />
|-
|KSHV-associated multicentric Castleman disease
|Significant vascular proliferation and hyalinization is seen in lymph nodes, with germinal centers surrounded by lymphocytes arranged in onion-skin appearance. <ref name=":16" />
|-
|[[Hodgkin Lymphomas|Hodgkin lymphoma]]
|Histologic features vary depending on CD4 count. In more severely immunocompromised individuals, there is a predominance of unfavorable histologic features (mixed cellularity and lymphocyte depletion), with unusually large proportions of Reed-Sternberg cells generally seen with EBV-coinfection. <ref name=":0" /><ref name=":14">{{Cite journal|last=Carbone|first=Antonino|last2=Gloghini|first2=Annunziata|last3=Serraino|first3=Diego|last4=Spina|first4=Michele|date=2009-01|title=HIV-associated Hodgkin lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/19339934|journal=Current opinion in HIV and AIDS|volume=4|issue=1|pages=3–10|doi=10.1097/COH.0b013e32831a722b|issn=1746-6318|pmid=19339934}}</ref> Nodular sclerosis subtype is mostly seen in patients with higher CD4 count. <ref name=":14" />
|}

==Immunophenotype==

Immunophenotype of lymphomas associated with HIV infection is displayed below:

{| class="wikitable sortable"
|-
!Lymphoma type!!Marker
|-
|[[Diffuse large B-cell lymphoma|DLBCL]]||CD10+ <ref>{{Cite journal|last=Dunleavy|first=Kieron|last2=Wilson|first2=Wyndham H.|date=2012-04-05|title=How I treat HIV-associated lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/22337719|journal=Blood|volume=119|issue=14|pages=3245–3255|doi=10.1182/blood-2011-08-373738|issn=1528-0020|pmc=3321851|pmid=22337719}}</ref>, CD20+ <ref name=":0" />, CD45+ <ref name=":15" />, CD30+, EBV+ <ref name=":15" />, LMP1+ <ref name=":15" />, BCL2+ <ref name=":15" />, BCL6+/- <ref name=":15" />, MUM1/IRF4+/- <ref name=":15" />, CD138+/- <ref name=":15" />
|-
|[[Burkitt Lymphoma|Burkitt lymphoma]]||CD20+ <ref name=":0" />, CD10+ <ref name=":0" />, BCL6+ <ref name=":3" />, EBV+/- <ref name=":3" />, BCL2- <ref name=":3" />, CD30- <ref name=":15" />
|-
|AIDS-related primary CNS lymphoma||CD10+ <ref name=":4" />, CD20+ <ref name=":0" />, BCL6+ <ref name=":4" />, MUM-1+ <ref name=":4" />, EBV+ <ref name=":0" />
|-
|Primary effusion lymphoma||CD45+ <ref name=":13" />, CD30+ <ref name=":13" />, CD38+ <ref name=":13" />, CD138+ <ref name=":15" />, IL-2 R beta <ref name=":13" />, EMA+ <ref name=":13" />, EBV+ <ref name=":0" />, HHV-8 <ref name=":0" />, CD19- <ref name=":13" />, CD20- <ref name=":0" />, CD79a- <ref name=":13" />, BCL6- <ref name=":15" />
|-
|[[Plasmablastic Lymphoma|Plasmablastic lymphoma]]
|EBV+ <ref name=":0" />, CD38+ <ref name=":2" />, CD138+ <ref name=":2" />, MUM/IRF41+ <ref name=":2" />, EMA+,CD20- <ref name=":0" />, CD79a- <ref name=":13" />, PAX5- <ref name=":15" />, CD45 - <ref name=":13" />
|-
|KSHV-associated multicentric Castleman disease
|HHV-8+ <ref name=":0" />, OCT2+ <ref name=":16" />, BLIMP1+ <ref name=":16" />, IRF4/MUM1+ <ref name=":16" /><ref name=":17">{{Cite journal|last=Carbone|first=Antonino|last2=Borok|first2=Margaret|last3=Damania|first3=Blossom|last4=Gloghini|first4=Annunziata|last5=Polizzotto|first5=Mark N.|last6=Jayanthan|first6=Raj K.|last7=Fajgenbaum|first7=David C.|last8=Bower|first8=Mark|date=2021-11-25|title=Castleman disease|url=https://pubmed.ncbi.nlm.nih.gov/34824298|journal=Nature Reviews. Disease Primers|volume=7|issue=1|pages=84|doi=10.1038/s41572-021-00317-7|issn=2056-676X|pmid=34824298}}</ref>, BCL6-<ref name=":17" />, CD138+/- <ref name=":17" />, CD79a- <ref name=":17" />, EBV-, PAX- <ref name=":16" />, BCL-6<ref name=":16" />
|-
|[[Hodgkin Lymphomas|Hodgkin lymphoma]]
|CD138+, LMP1+ <ref name=":14" />, MUM1 IRF4+ <ref name=":14" />, BCL6- <ref name=":14" />, EBV+ <ref name=":0" /><ref name=":14" />
|}
==Chromosomal Rearrangements (Gene Fusions)==
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
|-
|t(8;14)(q24;q32) <ref name=":0" /><ref name=":3" />
|
3'IGH::5'MYC <ref name=":7">{{Cite journal|title=t(8;14)(q24;q32) IGH/MYC|url=http://atlasgeneticsoncology.org/Anomalies/t0814ID1050.html}}</ref>
|der(14) <ref name=":7" />
|79.1% of overall HIV-related non-Hodgkin lymphomas <ref name=":6" />
|Unknown
|Unknown in lymphomas associated with HIV infection
|Unknown
|-
|t(14;18)(q32;q21) <ref name=":12">{{Cite journal|last=Philippe|first=Laure|last2=Lancar|first2=Remi|last3=Laurent|first3=Camille|last4=Algarte-Genin|first4=Michele|last5=Chassagne-Clément|first5=Catherine|last6=Fabiani|first6=Bettina|last7=Pierre Chenard|first7=Marie|last8=Lazure|first8=Thierry|last9=Parrens|first9=Marie|date=2020-02|title=In situ BCL2 expression is an independent prognostic factor in HIV-associated DLBCL, a LYMPHOVIR cohort study|url=https://pubmed.ncbi.nlm.nih.gov/31468517|journal=British Journal of Haematology|volume=188|issue=3|pages=413–423|doi=10.1111/bjh.16176|issn=1365-2141|pmid=31468517}}</ref>
|5'BCL2::3'IGH <ref name=":7" />
|der(14) <ref name=":7" />
|30% of HIV-associated DLBCL <ref name=":11">{{Cite journal|last=Dolcetti|first=Riccardo|last2=Gloghini|first2=Annunziata|last3=Caruso|first3=Arnaldo|last4=Carbone|first4=Antonino|date=2016-03-17|title=A lymphomagenic role for HIV beyond immune suppression?|url=http://dx.doi.org/10.1182/blood-2015-11-681411|journal=Blood|volume=127|issue=11|pages=1403–1409|doi=10.1182/blood-2015-11-681411|issn=0006-4971}}</ref>
|Unknown
|Poor prognosis in the setting of DLBCL and HIV infection <ref name=":12" />
|Unknown
|}

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

None of the lymphomas associated with HIV infection display specific individual region genomic gains, losses or regions of loss of heterozygosity.
==Characteristic Chromosomal Patterns==

No lymphomas associated with HIV infection display characteristic chromosomal-level changes.
==Gene Mutations (SNV/INDEL)==

{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC / TCGA / Other)'''
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
|-
|''TP53'' <ref name=":3" /><ref name=":13" />; SNV leading to missense or nonsense mutations
|TSG
|37% of HIV-related lymphomas <ref name=":6">{{Cite journal|last=Ballerini|first=P.|last2=Gaidano|first2=G.|last3=Gong|first3=J. Z.|last4=Tassi|first4=V.|last5=Saglio|first5=G.|last6=Knowles|first6=D. M.|last7=Dalla-Favera|first7=R.|date=1993-01-01|title=Multiple genetic lesions in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/8380252|journal=Blood|volume=81|issue=1|pages=166–176|issn=0006-4971|pmid=8380252}}</ref>
|Unknown
|Unknown in lymphomas associated with HIV infection
|Unknown
|-
|''BCL-6;'' SNV in the 5' noncoding region of BCL-2 <ref name=":10">{{Cite journal|last=Gaidano|first=G.|last2=Carbone|first2=A.|last3=Pastore|first3=C.|last4=Capello|first4=D.|last5=Migliazza|first5=A.|last6=Gloghini|first6=A.|last7=Roncella|first7=S.|last8=Ferrarini|first8=M.|last9=Saglio|first9=G.|date=1997-05-15|title=Frequent mutation of the 5' noncoding region of the BCL-6 gene in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/9160681|journal=Blood|volume=89|issue=10|pages=3755–3762|issn=0006-4971|pmid=9160681}}</ref>
|Oncogene
|58% of HIV-related lymphomas <ref name=":10" />
|Unknown
|Unknown in lymphomas associated with HIV infection
|Unknown
|-
|''PAX5'', ''RHO/TTF'', ''PIM1'': mutation occurs in 5' untranslated region overlapping with coding sequences <ref name=":8" />
|Oncogene
|50% of HIV-related lymphomas <ref name=":8" />
|Unknown
|Unknown in lymphomas associated with HIV infection
|Unknown
|-
|Ras family; activation of Ras family proto-oncogenesis by SNVs at codons 12,13, and 61 <ref name=":6" />
|Oncogene
|Infrequent <ref name=":6" />
|Unknown
|Unknown in lymphomas associated with HIV infection
|Unknown
|-
|''ID3'', ''TCF3'', ''CCND1:'' <ref name=":3" /> SNV leading to missense, nonsense, splice-site mutations
|Oncogene
|67% of HIV-associated Burkitt lymphoma <ref name=":3" />
|Unknown
|Unknown in lymphomas associated with HIV infection
|Unknown
|}
<br />

==Epigenomic Alterations==

None of the lymphomas associated with HIV infection display characteristic epigenomic alterations.

==Genes and Main Pathways Involved==

The main pathways involved in HIV-driven lymphomagenesis are described below:
{| class="wikitable sortable"
|-
!Pathway!!Pathophysiologic Outcome
|-
|NF-κB signaling
|In HIV-infected lymphoid cells, co-infection with EBV activates the NF-κB pathway via LMP-1, resulting in increased cell growth and decreased p53-induced apoptosis. In parallel apoptosis is also abrogated by enhanced expression of anti-apoptic proteins BCL2 and A20. <ref>{{Cite journal|last=Chao|first=Chun|last2=Silverberg|first2=Michael J.|last3=Martínez-Maza|first3=Otoniel|last4=Chi|first4=Margaret|last5=Abrams|first5=Donald I.|last6=Haque|first6=Reina|last7=Zha|first7=Hongbin D.|last8=McGuire|first8=Michelle|last9=Xu|first9=Lanfang|date=2012-09-01|title=Epstein-Barr virus infection and expression of B-cell oncogenic markers in HIV-related diffuse large B-cell Lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/22711707|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=18|issue=17|pages=4702–4712|doi=10.1158/1078-0432.CCR-11-3169|issn=1557-3265|pmc=3846529|pmid=22711707}}</ref>
|-
|pRb2/p130 signaling
|HIV-1 TaT binds to pRb2/p130, resulting in inactivation of its oncosuppressive features. This ultimately leads to the induction of oncogenes needed to proceed through the cell cycle including p107, cyclin A, and cyclin B. <ref name=":11" /><ref>{{Cite journal|last=De Falco|first=Giulia|last2=Bellan|first2=Cristiana|last3=Lazzi|first3=Stefano|last4=Claudio|first4=PierPaolo|last5=La Sala|first5=Domenico|last6=Cinti|first6=Caterina|last7=Tosi|first7=Piero|last8=Giordano|first8=Antonio|last9=Leoncini|first9=Lorenzo|date=2003-09-18|title=Interaction between HIV-1 Tat and pRb2/p130: a possible mechanism in the pathogenesis of AIDS-related neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/13679860|journal=Oncogene|volume=22|issue=40|pages=6214–6219|doi=10.1038/sj.onc.1206637|issn=0950-9232|pmid=13679860}}</ref><ref>{{Cite journal|last=Lazzi|first=Stefano|last2=Bellan|first2=Cristiana|last3=De Falco|first3=Giulia|last4=Cinti|first4=Caterina|last5=Ferrari|first5=Filomena|last6=Nyongo|first6=Aggrey|last7=Claudio|first7=Pier Paolo|last8=Tosi|first8=Gian Marco|last9=Vatti|first9=Rosella|date=2002-07|title=Expression of RB2/p130 tumor-suppressor gene in AIDS-related non-Hodgkin's lymphomas: implications for disease pathogenesis|url=https://pubmed.ncbi.nlm.nih.gov/12196924|journal=Human Pathology|volume=33|issue=7|pages=723–731|doi=10.1053/hupa.2002.125372|issn=0046-8177|pmid=12196924}}</ref>
|-
|DNA polymerase β
|HIV-1 TaT protein interacts with cellular transcription factors to increase the steady-state levels of DNA polymerase β in B-cells, resulting in increased and potentially oncogenic DNA recombination, leading to the development of lymphoma. <ref name=":11" /><ref>{{Cite journal|last=Srivastava|first=D. K.|last2=Tendler|first2=C. L.|last3=Milani|first3=D.|last4=English|first4=M. A.|last5=Licht|first5=J. D.|last6=Wilson|first6=S. H.|date=2001-03-09|title=The HIV-1 transactivator protein Tat is a potent inducer of the human DNA repair enzyme beta-polymerase|url=https://pubmed.ncbi.nlm.nih.gov/11242139|journal=AIDS (London, England)|volume=15|issue=4|pages=433–440|doi=10.1097/00002030-200103090-00001|issn=0269-9370|pmid=11242139}}</ref>
|-
|PI3K/Akt signaling activation
|The presence of HIV-1 matrix protein variant p17 has been demonstrated to activate the PI3K/Akt signaling pathway, resulting in increased B-cell proliferation. <ref>{{Cite journal|last=Giagulli|first=Cinzia|last2=Marsico|first2=Stefania|last3=Magiera|first3=Anna K.|last4=Bruno|first4=Rosalinda|last5=Caccuri|first5=Francesca|last6=Barone|first6=Ines|last7=Fiorentini|first7=Simona|last8=Andò|first8=Sebastiano|last9=Caruso|first9=Arnaldo|date=2011-03-14|title=Opposite effects of HIV-1 p17 variants on PTEN activation and cell growth in B cells|url=https://pubmed.ncbi.nlm.nih.gov/21423810|journal=PloS One|volume=6|issue=3|pages=e17831|doi=10.1371/journal.pone.0017831|issn=1932-6203|pmc=3056727|pmid=21423810}}</ref> S75X variants also upregulated LMP-1 expression, contributing to EBV-induced cell proliferation. <ref>{{Cite journal|last=Martorelli|first=Debora|last2=Muraro|first2=Elena|last3=Mastorci|first3=Katy|last4=Dal Col|first4=Jessica|last5=Faè|first5=Damiana Antonia|last6=Furlan|first6=Chiara|last7=Giagulli|first7=Cinzia|last8=Caccuri|first8=Francesca|last9=Rusnati|first9=Marco|date=2015-09-15|title=A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: implications for EBV-driven lymphomagenesis in the HIV setting|url=https://pubmed.ncbi.nlm.nih.gov/25704763|journal=International Journal of Cancer|volume=137|issue=6|pages=1374–1385|doi=10.1002/ijc.29494|issn=1097-0215|pmid=25704763}}</ref>
|-
|bFGF and VEGF-A; Activating mutations
|HIV1-TaT enhances the angiogenic activities of bFGF and VEGF-A, also activates the VEGF receptor 2 in HIV-related cancers, and results in development of HHV-8-related malignancies in the setting of HIV infection. Furthermore, viral IL-6, encoded by HHV-8, stimulates B cell growth and angiogenesis via VEGF-A in primary effusion lymphoma and KSHV-associated multicentric Castleman disease. <ref>{{Cite journal|last=Aoki|first=Yoshiyasu|last2=Tosato|first2=Giovanna|date=2003-06|title=Targeted inhibition of angiogenic factors in AIDS-related disorders|url=https://pubmed.ncbi.nlm.nih.gov/12769789|journal=Current Drug Targets. Infectious Disorders|volume=3|issue=2|pages=115–128|doi=10.2174/1568005033481222|issn=1568-0053|pmid=12769789}}</ref>
|-
|VCAM-1, E-selectin, ICAM-1 induction
|HIV-1 TaT can induce cell surface expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin and concurrently increase the expression of ICAM-1. This results in increased lymphoma cells migration and adhesion to endothelial cells in the context of Burkitt and primary effusion lymphomas. <ref>{{Cite journal|last=Chirivi|first=R. G.|last2=Taraboletti|first2=G.|last3=Bani|first3=M. R.|last4=Barra|first4=L.|last5=Piccinini|first5=G.|last6=Giacca|first6=M.|last7=Bussolino|first7=F.|last8=Giavazzi|first8=R.|date=1999-09-01|title=Human immunodeficiency virus-1 (HIV-1)-Tat protein promotes migration of acquired immunodeficiency syndrome-related lymphoma cells and enhances their adhesion to endothelial cells|url=https://pubmed.ncbi.nlm.nih.gov/10477700|journal=Blood|volume=94|issue=5|pages=1747–1754|issn=0006-4971|pmid=10477700}}</ref>
|-
|LMP-1 induction via IL-10 overexpression with suppression of T-cells and macrophages
|HIV-1 TaT can induce IL-10 gene expression, which contributes to oncogenicity of EBV by inducing LMP-1, in addition to causing immunosuppression of T-cells and macrophages. <ref>{{Cite journal|last=Wong|first=Hui-Lee|last2=Breen|first2=Elizabeth C.|last3=Pfeiffer|first3=Ruth M.|last4=Aissani|first4=Brahim|last5=Martinson|first5=Jeremy J.|last6=Margolick|first6=Joseph B.|last7=Kaslow|first7=Richard A.|last8=Jacobson|first8=Lisa P.|last9=Ambinder|first9=Richard F.|date=2010-04-24|title=Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the multicenter AIDS cohort study|url=https://pubmed.ncbi.nlm.nih.gov/20299965|journal=AIDS (London, England)|volume=24|issue=7|pages=1025–1033|doi=10.1097/QAD.0b013e328332d5b1|issn=1473-5571|pmc=3950937|pmid=20299965}}</ref><ref>{{Cite journal|last=Srivastava|first=D. K.|last2=Tendler|first2=C. L.|last3=Milani|first3=D.|last4=English|first4=M. A.|last5=Licht|first5=J. D.|last6=Wilson|first6=S. H.|date=2001-03-09|title=The HIV-1 transactivator protein Tat is a potent inducer of the human DNA repair enzyme beta-polymerase|url=https://pubmed.ncbi.nlm.nih.gov/11242139|journal=AIDS (London, England)|volume=15|issue=4|pages=433–440|doi=10.1097/00002030-200103090-00001|issn=0269-9370|pmid=11242139}}</ref>
|}
==Genetic Diagnostic Testing Methods==

*Fluorescence ''in situ'' hybridization (FISH)
*Chromosome analysis
*NGS

==Familial Forms==

N/A

==Additional Information==

N/A

==Links==

[[Diffuse Large B-cell Lymphoma, Not Otherwise Specified]]

[[Burkitt Lymphoma]]

[[Plasmablastic Lymphoma]]

[[Hodgkin Lymphomas]]

[[Primary Diffuse Large B-cell Lymphoma of the CNS|Primary Diffuse Large B-Cell Lymphoma of the CNS]]

==References==
<references />

==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.
<references />

HAEM4:Lymphomas Associated with HIV Infection - Revision history

Bailey.Glen at 21:42, 4 December 2023

Bailey.Glen at 18:58, 3 November 2023

Bailey.Glen: Created page with "==Primary Author(s)*== Patricia V. Hernandez, M.D., Washington University School of Medicine TOC ==Cancer Category/Type== Immunodeficiency-Associated Lymphoproliferati..."

@@ Line 1: / Line 1: @@
 ==Primary Author(s)*==
@@ Line 280: / Line 285: @@
 <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.
 <references />

HAEM4:Lymphomas Associated with HIV Infection - Revision history

Bailey.Glen at 21:42, 4 December 2023

Bailey.Glen at 18:58, 3 November 2023

Bailey.Glen: Created page with "==Primary Author(s)*== Patricia V. Hernandez, M.D., Washington University School of Medicine __TOC__ ==Cancer Category/Type== Immunodeficiency-Associated Lymphoproliferati..."

Bailey.Glen: Created page with "==Primary Author(s)*== Patricia V. Hernandez, M.D., Washington University School of Medicine TOC ==Cancer Category/Type== Immunodeficiency-Associated Lymphoproliferati..."