View source for Diffuse large B-cell lymphoma

{{Short description|Type of blood cancer}}
{{Infobox medical condition
| name = Diffuse large B cell lymphoma
| synonyms = '''DLBCL''' or '''DLBL'''
| image = Diffuse large B cell lymphoma - cytology low mag.jpg
| caption = [[Micrograph]] ([[Field stain]]) of a diffuse large B cell lymphoma.
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| field = [[Hematology]], [[oncology]], [[dermatology]]
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'''Diffuse large B-cell lymphoma''' ('''DLBCL''') is a [[cancer]] of [[B cell]]s, a type of [[lymphocyte]] that is responsible for producing [[antibody|antibodies]]. It is the most common form of [[non-Hodgkin lymphoma]] among adults,<ref name=Blood1997/> with an annual [[Incidence (epidemiology)|incidence]] of 7–8 cases per 100,000 people per year in the US and UK.<ref name=Morton2006/><ref name=Smith2011/> This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years,<ref name=Smith2011/> although it can occur in young adults and, in rare cases, children.<ref name=Smith2010/> DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy.<ref name=Kumar2009/> The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic [[B symptoms]], e.g. [[fever]], [[Cachexia|weight loss]], and [[night sweats]].<ref name=UpToDateEpi2012/>

The causes of diffuse large B-cell lymphoma are not well understood. Usually DLBCL arises from normal B cells, but it can also represent a [[malignant transformation]] of other types of lymphoma (particularly [[marginal zone lymphoma]]s<ref name="pmid28288708">{{cite journal | vauthors = Casulo C, Friedberg J | title = Transformation of marginal zone lymphoma (and association with other lymphomas) | journal = Best Practice & Research. Clinical Haematology | volume = 30 | issue = 1–2 | pages = 131–138 | date = 2017 | pmid = 28288708 | doi = 10.1016/j.beha.2016.08.029 }}</ref>) or, in rare cases termed [[Richter's transformation]], [[chronic lymphocytic leukemia]].<ref name="pmid29524963">{{cite journal | vauthors = Abuelgasim KA, Rehan H, Alsubaie M, Al Atwi N, Al Balwi M, Alshieban S, Almughairi A | title = Coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma with antecedent chronic lymphocytic leukemia: a case report and review of the literature | journal = Journal of Medical Case Reports | volume = 12 | issue = 1 | pages = 64 | date = March 2018 | pmid = 29524963 | pmc = 5845776 | doi = 10.1186/s13256-018-1612-4 | doi-access = free }}</ref> An underlying [[immunodeficiency]] is a significant risk factor for development of the disease.{{sfn|Swerdlow|Campo|Jaffe|Pileri|2008|p=233}} Infections with the [[Epstein–Barr virus]] (EBV),<ref name="pmid29984868">{{cite journal | vauthors = Castillo JJ, Beltran BE, Miranda RN, Young KH, Chavez JC, Sotomayor EM | title = EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2018 update on diagnosis, risk-stratification and management | journal = American Journal of Hematology | volume = 93 | issue = 7 | pages = 953–962 | date = July 2018 | pmid = 29984868 | doi = 10.1002/ajh.25112 | doi-access = free | hdl = 20.500.12727/6261 | hdl-access = free }}</ref><ref name="pmid25999451">{{cite journal | vauthors = Nicolae A, Pittaluga S, Abdullah S, Steinberg SM, Pham TA, Davies-Hill T, Xi L, Raffeld M, Jaffe ES | title = EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment | journal = Blood | volume = 126 | issue = 7 | pages = 863–72 | date = August 2015 | pmid = 25999451 | pmc = 4536540 | doi = 10.1182/blood-2015-02-630632 }}</ref> [[Kaposi's sarcoma-associated herpesvirus]],<ref name="pmid31735345">{{cite journal | vauthors = Sukswai N, Lyapichev K, Khoury JD, Medeiros LJ | title = Diffuse large B-cell lymphoma variants: an update | journal = Pathology | volume = 52| issue = 1| pages = 53–67| date = November 2019 | pmid = 31735345 | doi = 10.1016/j.pathol.2019.08.013 | s2cid = 208142227 | doi-access =  }}</ref><ref name="pmid30154110">{{cite journal | vauthors = Shimada K, Hayakawa F, Kiyoi H | title = Biology and management of primary effusion lymphoma | journal = Blood | volume = 132 | issue = 18 | pages = 1879–1888 | date = November 2018 | pmid = 30154110 | doi = 10.1182/blood-2018-03-791426 | doi-access = free }}</ref> [[human immunodeficiency virus]] (i.e. HIV),<ref name="pmid31735345"/> and the ''[[Helicobacter pylori]]'' bacterium<ref name="pmid28288708"/> are also associated with the development of certain subtypes of diffuse large B-cell lymphoma. However, most cases of this disease are associated with the unexplained step-wise acquisition of increasing numbers of gene mutations and changes in gene expression that occur in, and progressively promote the malignant behavior of, certain B-cell types.<ref name="pmid30859597">{{cite journal | vauthors = Liu Y, Barta SK | title = Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment | journal = American Journal of Hematology | volume = 94 | issue = 5 | pages = 604–616 | date = May 2019 | pmid = 30859597 | doi = 10.1002/ajh.25460 | doi-access = free }}</ref>

[[Medical diagnosis|Diagnosis]] of DLBCL is made by removing a portion of the tumor through a [[biopsy]], and then examining this tissue using a microscope. Usually a [[Hematopathology|hematopathologist]] makes this diagnosis.{{sfn|Goldman|Schafer|2012|p=1222}} Numerous subtypes of DLBCL have been identified which differ in their clinical presentations, biopsy findings, aggressive characteristics, [[Prognosis|prognoses]], and recommended treatments.<ref name="pmid26980727">{{cite journal | vauthors = Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES | title = The 2016 revision of the World Health Organization classification of lymphoid neoplasms | journal = Blood | volume = 127 | issue = 20 | pages = 2375–90 | date = May 2016 | pmid = 26980727 | pmc = 4874220 | doi = 10.1182/blood-2016-01-643569 }}</ref> However, the usual treatment for most subtypes of DLBCL is [[chemotherapy]] combined with a [[Monoclonal antibody therapy|monoclonal antibody drug that targets the disease's cancerous B-cells]], usually [[rituximab]].{{sfn|Goldman|Schafer|2012|p=1225}} Through these treatments, more than half of all patients with DLBCL can be cured;<ref name=Akyurek2011/> the overall cure rate for older adults is less than this but their [[five-year survival rate]] has been around 58%.<ref name=Feugier2005/>

== Subtypes of diffuse large B-cell lymphoma ==
Diffuse large B-cell lymphoma encompasses a biologically and clinically diverse set of disease subtypes,<ref name=Alizadeh2000/> many of which are difficult to separate from one another based on well-defined and widely accepted criteria. The [[World Health Organization]], 2008, classification system defined more than a dozen subtypes,{{sfn|Swerdlow|Campo|Jaffe|Pileri|2008|pp=233–7}} each of which was identified based on the location of the tumor, the presence of other cell types such as [[T cell]]s in the tumor, and whether the patient had certain other illnesses related to DLBCL. Based on further research, the World Health Organization, 2016, reclassified DLBCL into its most common subtype, diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). DLBCL, NOS represents 80–85% of all DLBCL.<ref name="pmid29167021">{{cite journal | vauthors = Li S, Young KH, Medeiros LJ | title = Diffuse large B-cell lymphoma | journal = Pathology | volume = 50 | issue = 1 | pages = 74–87 | date = January 2018 | pmid = 29167021 | doi = 10.1016/j.pathol.2017.09.006 | s2cid = 20839613 | url = http://www.intechopen.com/articles/show/title/diffuse-large-b-cell-lymphoma | url-access = subscription }}{{Dead link|date=March 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> The remaining DLBCL cases consist of relatively rare subtypes that are distinguished by their [[Morphology (biology)|morphology]], (i.e. microscopic appearance), [[Immunophenotyping|immunophenotype]], (i.e. expression of certain marker proteins), clinical findings, and/or association with certain [[pathogenic]] [[virus]]es.<ref name="pmid31735345"/> Some cases of DLBCL, NOS, while not included in the 2016 World Health Organization's classification, are clearly associated with, and caused by, chronic infection by the [[bacterium]], [[Helicobacter pylori#Diffuse large B-cell lymphoma|''Helicobacter pylori'']].<ref name="pmid31455250">{{cite journal | vauthors = Cheng Y, Xiao Y, Zhou R, Liao Y, Zhou J, Ma X | title = Prognostic significance of helicobacter pylori-infection in gastric diffuse large B-cell lymphoma | journal = BMC Cancer | volume = 19 | issue = 1 | pages = 842 | date = August 2019 | pmid = 31455250 | pmc = 6712724 | doi = 10.1186/s12885-019-6067-5 | doi-access = free }}</ref>

=== Diffuse large B-cell lymphoma, not otherwise specified ===
DLBCL cases that do not fit the distinctive clinical presentation, tissue morphology, neoplastic cell [[phenotype]], and/or pathogen-associated criteria of other DLBCL subtypes are termed Diffuse large B-cell lymphoma, not otherwise specified: DLBCL, NOS, while representing 80–85% of all DLBCL cases, is a [[diagnosis of exclusion]]. In general, DLBCL, NOS is an aggressive disease with an overall long-term survival rate in patients treated with standard chemotherapy regimens of ~65%. However, this disease has many variants that differ not only in the just cited parameters but also in their aggressiveness and responsiveness to treatment.<ref name="pmid30380402">{{cite journal | vauthors = Grimm KE, O'Malley DP | title = Aggressive B cell lymphomas in the 2017 revised WHO classification of tumors of hematopoietic and lymphoid tissues | journal = Annals of Diagnostic Pathology | volume = 38 | pages = 6–10 | date = February 2019 | pmid = 30380402 | doi = 10.1016/j.anndiagpath.2018.09.014 | s2cid = 53196244 }}</ref>

==== Presenting signs and symptoms ====
About 70% of DLBCL, NOS cases present primarily with lymph node disease. In these cases, the most typical presenting symptom at the time of diagnosis is a mass that is rapidly enlarging and located in a part of the body with multiple lymph nodes such as the groin, arm pits, or neck. In the remaining ~30% of other cases, the disease begins as an extranodal lymphoma, most commonly in the stomach,<ref name="pmid31735345"/> or, less commonly, in other sites such as the testicles, breasts, uterus, ovaries, kidneys, [[adrenal gland]]s, thyroid gland, or bone.<ref name="pmid29931605">{{cite journal | vauthors = Ollila TA, Olszewski AJ | title = Extranodal Diffuse Large B Cell Lymphoma: Molecular Features, Prognosis, and Risk of Central Nervous System Recurrence | journal = Current Treatment Options in Oncology | volume = 19 | issue = 8 | pages = 38 | date = June 2018 | pmid = 29931605 | pmc = 6294323 | doi = 10.1007/s11864-018-0555-8 }}</ref> The presenting signs and symptoms in these cases reflect the presence of a rapidly expanding tumor or infiltrate that produces symptoms specific to the organ of involvement such as increased size, pain, and/or dysfunction.<ref name="pmid29931605"/> Individuals with nodal or extranodal disease also present with: systemic [[B symptoms]] such as weight loss, night sweats, fevers, and/or fatigue in ~33% of cases; unexplained elevations in their blood levels of [[lactic acid dehydrogenase]] and [[beta-2 microglobulin]] in many cases; malignant cells infiltrating their [[bone marrow]] in 10–20% of cases; and/or localized [[Ann Arbor staging#Principal stages|Stage I or II disease]] in up to 50% of cases and disseminated [[Ann Arbor staging#Principal stages|Stage III or IV disease]] in the remaining cases.<ref name="pmid31735345"/> Bone marrow involvement may be due to DLBCL, NOS cells or low grade lymphoma cells; only DLBCL, NOS cell infiltrates indicate a worse prognosis.<ref name="pmid29167021"/> Uncommonly, DLBCL may arise as a transformation of [[marginal zone lymphoma]] (MZL) in individuals who have been diagnosed with this indolent cancer 4–5 years (median times) previously.<ref name="pmid28288717">{{cite journal | vauthors = Pileri S, Ponzoni M | title = Pathology of nodal marginal zone lymphomas | journal = Best Practice & Research. Clinical Haematology | volume = 30 | issue = 1–2 | pages = 50–55 | date = 2017 | pmid = 28288717 | doi = 10.1016/j.beha.2016.11.001 }}</ref>

===== Prognostic indicators based on clinical presentation =====
The [[International Prognostic Index#International Prognostic Index|International Prognostic Index]] and more recently, the Index's [[International Prognostic Index#Age-Adjusted IPII|age-adjusted variant]] use age >60 years, elevated serum [[lactate dehydrogenase]] levels, low [[Performance status#ECOG/WHO/Zubrod score|performance status]], and involvement in more than one extranodal site as contributors to a poor prognosis in patients with DLBCL, NOS.<ref name="pmid29167021"/> In addition, disease that initially involves the testes, breast, or uterus has a relatively high rate of spreading to the [[central nervous system]] while disease initially involving the kidneys, [[adrenal glands]], ovaries, or bone marrow has a high rate of spreading to other organs, including the central nervous system. All of these cases as well as cases initially involving the central nervous system have relatively poor to very poor prognoses. Cases initially involving the stomach, thyroid, or a single bone site have relatively good prognoses.<ref name="pmid29931605"/>

==== Pathophysiology ====
Most cases of DLBCL, NOS appear to result at least in part from the step-wise development of [[gene]] changes such as [[mutations]], [[Regulation of transcription in cancer|altered expressions]], [[Gene amplification|amplifications]] (i.e. increases in the number of copies of specific genes), and [[Chromosomal translocation|translocations]] from normal sites to other chromosomal sites. These changes often result in gains or loses in the production or function of [[Gene product|the product of these genes]] and thereby the activity of [[cell signaling]] pathways that regulate the [[Cellular differentiation|maturation]], [[Cell growth|proliferation]], survival, spread, [[Immune system#Tumor immunology|evasion of the immune system]], and other malignant behaviors of the cells in which they occur. While scores of genes have been reported to be altered in DLBCL, NOS many of these may not contribute to DLBCL, NOS. Changes in the following genes occur frequently in, and are suspected of contributing to, this disease's development and/or progression.<ref name="pmid30859597"/>
* ''[[Bcl-2|BCL2]]'': This gene is a [[Oncogene#Proto-oncogene|proto-oncogene]], i.e. a normal gene that can become cancer-causing when mutated or overexpressed. Its product, Bcl-2 protein, regulates cellular [[apoptosis]] by inhibiting the apoptosis-causing proteins, [[Bcl-2-associated X protein]] and [[Bcl-2 homologous antagonist killer]].<ref name="pmid31287161"/>
* ''[[BCL6]]'': This genes' product, Bcl-6, is a [[repressor]] of transcription that regulates the expression of other genes which control cell maturation, proliferation, and survival.<ref name="pmid31287161"/>
* ''[[MYC]]'': This proto-oncogene's product, Myc, encodes a [[transcription factor]] which regulates the expression of other genes whose products stimulate cell proliferation and expansion to extra-nodal tissues.<ref name="pmid28985567">{{cite journal | vauthors = Anupama R, Zhang J | title = Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma | journal = Cell | volume = 171 | issue = 2 | pages = 481–494 | date = October 2017 | pmid = 28985567 | pmc = 5659841 | doi = 10.1016/j.cell.2017.09.027 }}</ref>
* ''[[EZH2]]'': This gene's product, the EZH2 protein, is a [[Histone methyltransferase|histone-lysine N-methyltransferase]]. It thereby regulates the expression of other genes which control lymphocyte maturation.<ref name="pmid29167021"/>
* ''[[MYD88]]'': This gene's product is a [[signal transducing adaptor protein]] essential for the [[Signal transduction|transduction]] of [[Interleukin-1 receptor|interleukin-1]] and [[toll-like receptor]] signaling pathways. It thereby regulates [[NF-κB]] and [[MAPK/ERK pathway|MAPK/ERK signaling pathways]] that control cell proliferation and survival.<ref name="pmid31287161"/>
* ''[[CREBBP]]'': This gene's product is a transcriptional [[coactivation (Transcription)|coactivator]]; it activates numerous [[transcription factor]]s, some of which control cell proliferation.<ref name="pmid30859597"/>
* ''[[CD79A]]'' and ''[[CD79B]]'': these genes' products are critical components of the [[B-cell receptor]]. Mutations in either gene can cause uncontrolled cell activation and proliferation.<ref name="pmid30859597"/>
* ''[[PAX5]]'': this gene's product, Pax-5, is a transcription factor that controls the development, maturation, and survival of B-cells; it also controls expression of the ''MYC'' gene in these cells.<ref name="pmid25428382">{{cite journal | vauthors = Shahjahani M, Norozi F, Ahmadzadeh A, Shahrabi S, Tavakoli F, Asnafi AA, Saki N | title = The role of Pax5 in leukemia: diagnosis and prognosis significance | journal = Medical Oncology (Northwood, London, England) | volume = 32 | issue = 1 | pages = 360 | date = January 2015 | pmid = 25428382 | doi = 10.1007/s12032-014-0360-6 | s2cid = 7127158 }}</ref>

As a consequence of these gene changes and possibly other changes that have not yet been identified, the neoplastic cells in DLBCL, NOS exhibit pathologically overactive NF-κB, [[PI3K/AKT/mTOR pathway|PI3K/AKT/mTOR]], [[JAK-STAT signaling pathway|JAK-STAT]]0, [[MAPK/ERK pathway|MAPK/ERK]], [[B-cell receptor#Signaling pathways of the B-cell receptor|B-cell receptor]], [[Toll-like receptor#Function|toll-like receptor]], and [[NF-κB#Signaling|NF-κB]] signaling pathways and thereby uncontrolled pro-malignant behaviors.<ref name="pmid31287161"/>

==== Diagnosis ====
Microscopic examinations of involved tissues reveal large neoplastic cells that are typically classified as B-cells based on their expression of B-cell marker proteins (e.g. [[CD20]], [[CD19]], [[CD22]], [[CD79]], PAX5, [[POU2AF1|BOB1]], [[SLC22A2|OCT2]], an [[immunoglobulin]] [usually [[IgM]] but occasionally [[Immunoglobulin G|IgG]] or [[IgA]])],<ref name="pmid31735345"/> [[CD30]], and in ~20–25% of cases [[PD-L1]] or [[PD-L2]] (PD-L1 and PD-L2 are [[transmembrane protein]]s that normally function to suppress attack by the immune system).<ref name="pmid29167021"/> These cells arrange in a diffuse pattern, efface the tissues' architecture, and resemble [[Centroblast]] cells (80% of cases), [[Immunoblast]] cells (8–10% of cases), or [[Anaplasia|anaplastic]] cells (9% of cases; anaplastic cells have bizarre nuclei and other features that may mimic the [[Reed–Sternberg cells]] of [[Hodgkin disease]] or the neoplastic cells of [[anaplastic large cell lymphoma]]). Rarely, these neoplastic cells are characterized as having signet ring or spindle shaped nuclei, prominent [[cytoplasm]]ic granules, multiple [[microvillus]] projections, or, when viewed by [[electron microscopy]], [[tight junctions|tight junctions with other cells]].<ref name="pmid31735345"/> These neoplastic tissue infiltrates are often accompanied by small non-malignant [[T-cell|T-cell lymphocytes]] and [[histiocytes]] that have a reactive morphology.<ref name="pmid29167021"/>

==== Variants of DLBCL, NOS ====
The World Health Organization, 2016, requires that the neoplastic cells in DLBCL, NOS be further defined based on whether they are derived from [[germinal center]] B-cells (i.e. GBC) or activated B-cells (i.e. ABC) as identified by [[gene expression profiling]] (GEP) or are GBC or non-GBC as identified by [[immunohistochemistry|immunohistochemical]] (IHC) analyses. As identified by GEP, which measures all cellular [[messenger RNA]]s, GBC and ABC represent about 50 and ~35% of DLBCL, NOS cases, respectively, with ~15% of cases being unclassifiable.<ref name="pmid29126866">{{cite journal | vauthors = Cabanillas F, Shah B | title = Advances in Diagnosis and Management of Diffuse Large B-cell Lymphoma | journal = Clinical Lymphoma, Myeloma & Leukemia | volume = 17 | issue = 12 | pages = 783–796 | date = December 2017 | pmid = 29126866 | doi = 10.1016/j.clml.2017.10.007 | s2cid = 25304758 }}</ref> IHC analyses measure the cellular expression of specific proteins using a panel of fluorescent antibodies that bind to and therefore stain a set of key proteins. For example, one commercially available panel uses three antibodies to detect CD10, BCL6, and MUM1 proteins; GBC express whereas ABC and unidentified cells do not express these proteins; accordingly, this as well as other IHC panels classify ABC and undetermined neoplastic cell types together as non-GBC.<ref name="pmid31287161">{{cite journal | vauthors = Abramson JS | title = Hitting back at lymphoma: How do modern diagnostics identify high-risk diffuse large B-cell lymphoma subsets and alter treatment? | journal = Cancer | volume = 125 | issue = 18 | pages = 3111–3120 | date = September 2019 | pmid = 31287161 | doi = 10.1002/cncr.32145 | doi-access = free }}</ref> Individuals with the ABC, unclassifiable, and non-GBC variants have significantly worse prognoses than individuals with the GBC variant:<ref name="pmid30380402"/> respective 5 year [[Progression-free survival|progression-free]] and [[Survival rate#Overall survival rates|overall survival rates]] have been reported to be 73–80% for GBC variants and 31–56% for ABC variants. Clinically, however, most DLBCL, NOS cases are analyzed by IHC and therefore classified as either GBC or non-GBC variants with non-GBC variants having progression-free and overall survival rates similar to those of the ABC variants.<ref name="pmid29167021"/>

Gene and protein [[Biomarker|markers]] in the neoplastic cells of DLBCL, NOS that have clinical significance include [[CD5 (protein)|CD5]], ''MYC'', ''BCL2'', BCL6,<ref name="pmid31735345"/> CD20, CD19, CD22, CD30, PD-L1, and PD-L2.<ref name="pmid30380402"/> The 5–10% of DLBCL, NOS cases in which the neoplastic cells express CD5 have a very poor prognosis that is not improved by even aggressive treatment regimens. Cases in which [[fluorescence in situ hybridization]] analysis show that the neoplastic cells' in this disease bear [[chromosomal translocation|translocations]] in both the ''MYC'' and ''BCL2'' genes or ''MYC'' and ''BCL6'' genes (termed double hit lymphomas) or in all three genes (termed triple hit lymphomas)<ref name="pmid29167021"/> are associated with advanced disease that spreads to the [[central nervous system]].<ref name="pmid29909914">{{cite journal | vauthors = Chavez JC, Locke FL | title = CAR T cell therapy for B-cell lymphomas | journal = Best Practice & Research. Clinical Haematology | volume = 31 | issue = 2 | pages = 135–146 | date = June 2018 | pmid = 29909914 | pmc = 6716161 | doi = 10.1016/j.beha.2018.04.001 }}</ref> These lymphomas, termed high-grade B-cell lymphoma with ''MYC, BL2,'' and/or ''BL6'' rearrangements or, more simply, DH/THL, are regarded as borderline DLBCL, NOS.<ref name="pmid29167021"/> They represent 6–14% of all DLBCL, NOS and have had long-term survival rates of only 20–25%.<ref name="pmid29931605"/> Another variant B-cell lymphoma that is also considered to be a borderline DLBCL, NOS is termed high-grade B-cell lymphoma, not otherwise specified (HGBCL, NOS).<ref name="pmid29167021"/> These two aggressive borderline B-cell lymphomas were previously grouped together as "B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt lymphoma" (i.e. BCLU) but were separated into DH/THL and HGBC, NOS by the World Health Organization, 2016.<ref name="pmid26980727"/> The neoplastic cells in a related variant, double expresser lymphoma (i.e. DEL), express the products of ''MYC'' and ''BCL2'' genes, i.e. c-Myc and bcl-2 proteins, respectively, but do not have translocations in either of their genes. DEL, which represents about one-third of all DLBCL, NOS cases, has a poorer prognosis than standard DLBCL, NOS but not as poor as DH/THL cases.<ref name="pmid29167021"/><ref name="pmid29126866"/> Cases in which the neoplastic cells have alterations in the ''MYC'' gene or its expression without changes in ''BLC2'' or ''BLC6'' also have a poor prognosis,<ref name="pmid29167021"/> particularly in cases where the ''MYC'' gene [[Chromosomal translocation|translocates]] (i.e. rearranges) with one of the [[V(D)J recombination#Immunoglobulins|immunoglobulin gene loci]]. DLBCL that begin in the testicles are a variant of DLBCL, NOS that some authors suggest should be classified as a distinct DLBCL subtype.<ref name="pmid31735345"/> This variant, termed [[Primary testicular diffuse large B-cell lymphoma]] (PT-DLBCL), is a DLBCL, NOS that in >75% of cases involves activated B-cells, i.e. ABC.<ref name="pmid29289361">{{cite journal | vauthors = ((Twa DDW)), Mottok A, Savage KJ, Steidl C | title = The pathobiology of primary testicular diffuse large B-cell lymphoma: Implications for novel therapies | journal = Blood Reviews | volume = 32 | issue = 3 | pages = 249–255 | date = May 2018 | pmid = 29289361 | doi = 10.1016/j.blre.2017.12.001 }}</ref> These cells, which typically have a [[centroblast]]-like morphology, infiltrate one or, in ~6% of cases, both [[testicles]]. PT-DLBCL is an aggressive disease that often spreads to the [[central nervous system]]<ref name="pmid29289361"/> and has median overall survival and progression-free survival times of 96 and 49 months, respectively.<ref name="pmid31735345"/>

The neoplastic cells in almost all cases of DLBCL, NOS express CD20. Commercially available anti-CD20 antibody agents such as [[rituximab]] or [[Obinutuzumab]] (which is sometimes used in place of rituximab) kill cells that express high levels of CD20 by binding to this cell-surface protein and thereby targeting them for attack by the hosts [[adaptive immune system]]. The addition of one of these [[immunotherapy]] agents to [[chemotherapy]] protocols has greatly improved the prognosis of most DLBCL, NOS variants.<ref name="pmid29167021"/> Neoplastic cell expression of CD30, found in 10–15% of DLBCL, NOS cases is a favorable prognostic indicator. As indicated in the following Treatments and prognoses section, expression of the CD20 and CD30 proteins as well as the CD19, CD20 CD22, CD30, CD79A, CD79B, and D-L1 proteins, expression of the ''MYC'', ''BCL2'', ''MYD88nd'', and ''CREBBP'' genes, and expression of the PI3K/AKT/mTOR, JAK-STAT, B-cell receptor, toll-like receptor, and NF-κB signaling pathways are being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC DLBCL, NOS cases.<ref name="pmid30859597"/><ref name="pmid29167021"/>

==== Treatments and prognoses ====
===== First-line therapy =====
First-line therapy for patients with the GBC variant of DLBCL, NOS is [[R-CHOP]]. R-CHOP consists of rituximab, three chemotherapy drugs ([[cyclophosphamide]], [[doxorubicin]], and [[vincristine]]) and a [[glucocorticoid]] (either [[prednisone]] or [[prednisolone]]).<ref name="pmid29126866"/> The regimen achieves cure, relapse following [[Remission (medicine)|remission]],<ref name="pmid29167021"/> and unresponsive rates of 60–70%, 30–40% and <10%, respectively, in GBC variant cases.<ref name="pmid29808921">{{cite journal | vauthors = Gisselbrecht C, Van Den Neste E | title = How I manage patients with relapsed/refractory diffuse large B cell lymphoma | journal = British Journal of Haematology | volume = 182 | issue = 5 | pages = 633–643 | date = September 2018 | pmid = 29808921 | pmc = 6175435 | doi = 10.1111/bjh.15412 }}</ref> Relapses generally occur within the first 3 years of diagnosis with few cases doing so after 5 years. Patients who are refractory to, relapse within 1 year of diagnosis before starting, relapse within 6 months after completing, or progress within 2 years of starting R-CHOP have poorer prognoses.<ref name="pmid29909914"/> R-CHOP is less effective and not recommended for patients who have ''MYC, BL2,'' and/or ''BL6'' rearrangements regardless of their GBC, ABC, or non-GBC type. One recommendation for treating these DH/THL cases is the [[EPOCH (chemotherapy)|DA-R-EPOCH]] regimen (dose-adjusted rituximab, [[etoposide]], prednisolone, oncovin, cyclophosphamide, and hydroxydaunorubicin). S-R-EPOCH achieves 2 year survival rates of 40–67% compared to a ~25% survival rate for R-CHOP in these cases.<ref name="pmid29126866"/> DA-R-EPOCH has also been recommended for patients with double expresser lymphoma<ref name="pmid29126866"/> although some experts recommend treating this variant more like a typical DLCBL, NOS.<ref name="pmid31287161"/> First-line therapy for patients with the ABC, undetermined, or non-GBC variants has been the DA-R-EPOCH regimen. Patients with these variants (including those with double expresser lymphoma) have had a ~40% cure rate when treated with it.<ref name="pmid29126866"/> A [[randomized clinical trial]] conducted in France reported that a R-ACVBP chemotherapy regimen (rituximab, [[adriamycin]], cyclophosphamide, [[vindesine]], [[bleomycin]], and [[cytarabine]] followed by sequential [[Therapy#By intent|consolidation therapy]] with systemic [[methotrexate]], [[ifosfamide]], and [[etoposide]], and then cytarabine) achieved significantly better response rates than R-CHOP in ABC/NGC variant cases lymphoma.<ref name="pmid31287161"/> In DLBCL, NOS variants which trend to spread or to the central nervous system, methotrexate has been recommended to be added to regimens not containing it for use as [[Preventive healthcare|prophylaxis]] to reduce the incidence of this complication.<ref name="pmid29909914"/> The role of [[Autologous stem-cell transplantation]] as an addition to first-line therapy in the treatment of DLBCL, NOS, including cases with a poor prognosis, is unclear.<ref name="pmid30859597"/>

A [[Phases of clinical research#Summary|phase I clinical research trial]] found that the addition of [[lenalidomide]] to the R-CHOP regimen produce an ~80% complete response rate in GBC as well as non- GBC DLBCL, NOS variants.<ref name="pmid30859597"/> Two [[Phases of clinical research#Summary|phase III clinical research trials]] are underway to confirm these results and determine if the R-CHOP + lenalidomide regimen is superior to R-CHOP in the up-front treatment of GBC and/or non-GBC variants.<ref name="pmid30859597"/>

===== Treatment of recurrent and refractory DLBCL, NOS =====
Patients with DLBCL, NOS who relapse or progress following first-line therapy have been treated with "salvage regimens" consisting of high-dose (also termed high-intensity) [[chemotherapy]] conditioning drugs followed by [[Hematopoietic stem cell transplantation#Autologous|autologous stem cell transplantation]]. This regimen has attained 3-year progression-free survival rates of 21–37%.<ref name="pmid30859597"/> Relapse following this treatment carries a very poor prognosis with median overall survival times of ~10 months.<ref name="pmid29909914"/> Patients who have failed or because of health issues are ineligible for autologous stem cell transplantation have been treated with low-dose (i.e. low-intensity) chemotherapy conditioning regimens followed by [[Hematopoietic stem cell transplantation#Allogeneic|allogeneic stem cell transplantation]]. This regimen has achieved 3 year progression-free and overall survival rates of 41% and 52%, respectively.<ref name="pmid29808921"/> Further studies are underway to determine the best treatment regimens for these cases.<ref name="pmid30859597"/><ref name="pmid29808921"/> Patients refractory to first-line therapy or who relapse within 12 months of receiving ''salvage'' therapy (including bone marrow transplant) for recurrent disease have had poor prognoses with median overall survival rates of 3.3 and 6.3 months, respectively.<ref name="pmid30859597"/> The prognosis of these patients appears to be improved by using CAR-T therapy.

Chimeric antigen receptor T cell (i.e. CAR-T) [[Adoptive immunity|adoptive cellular immunotherapy]] has emerged as a recent advance in treating refractory and relapsed DLBCL, NOS ([[tisagenlecleucel]], [[axicabtagene ciloleucel]], [[lisocabtagene maraleucel]]). Chimeric antigen receptor T cells are [[Genetic engineering|genetically engineered]] to express: '''1)''' an artificial [[T-cell receptor]] consisting of antigen-recognition and attached hinge domains expressed on their [[Cell membrane|surface membranes]]; '''2)''' a surface membrane-spanning domain; '''3)''' an intracellular domain which, when the antigen-recognition domain binds its targeted antigen, activates signaling pathways that cause the T-cell to attack and kill cells that bear the recognized antigen on their surface membranes; and '''4)''', in more recently devised second generation CAR-T strategies, an associated intracellular co-stimulating molecule (e.g. [[CD28]] or [[CD137|4-1BB]]) which augments activation of the cell-killing signaling pathways. CAR-T therapy, as it pertains to DLBCL, NOS, kills a patient's neoplastic B-cells by isolating this patient's [[T-cell]]s; [[Genetic engineering|genetically engineering]] these cells to express an artificial [[T-cell receptor]] designed to bind an [[antigen]] expressed on the surface of their neoplastic B-cells; and infusing these cells back into the donor patient. The targeted antigen has usually been [[CD19]], a surface membrane protein expressed on virtually all B-cells including the neoplastic cells in DLBCL, NOS.<ref name="pmid29909914"/> However, design of CARs<ref name="pmid30830661">{{cite journal | vauthors = Lee YH, Kim CH | title = Evolution of chimeric antigen receptor (CAR) T cell therapy: current status and future perspectives | journal = Archives of Pharmacal Research | volume = 42 | issue = 7 | pages = 607–616 | date = July 2019 | pmid = 30830661 | doi = 10.1007/s12272-019-01136-x | s2cid = 73475110 }}</ref> as well as the antigens chosen to be their targets <ref name="pmid29909914"/> are constantly being changed in order to improve the efficacy of this therapeutic strategy.

CAR-T therapy for DLBCL, NOS has been used on patients who are refractory to and/or have progressed on first-line as well as salvage (including autologous stem cell transplantation) treatment regimens. Patients are treated first with a conditioning chemotherapy regimen, usually cyclophosphamide and [[fludarabine]], and then infused with their own T-cells that have been engineered to attack CD19-bearing or, rarely, [[CD20]]-bearing cells. A [[meta-analysis]] of 17 studies using this or very similar approaches to treat DLBCL, NOS found the treatments gave complete and partial responses rates of 61% and 43%, respectively. While these studies did not have control groups and were too recent for meaningful estimates of remission durations, the remission rates were higher than expected using other treatment approaches. Significant and potentially lethal therapeutic complications of this therapy included development of the [[cytokine release syndrome]] (21% of cases), neurotoxicity, i.e. the CAR-T cell-related encephalopathy syndrome (9% of cases),<ref name="pmid31923107">{{cite journal | vauthors = Zheng XH, Zhang XY, Dong QQ, Chen F, Yang SB, Li WB | title = Efficacy and safety of chimeric antigen receptor-T cells in the treatment of B cell lymphoma: a systematic review and meta-analysis | journal = Chinese Medical Journal | volume = 133 | issue = 1 | pages = 74–85 | date = January 2020 | pmid = 31923107 | doi = 10.1097/CM9.0000000000000568 | pmc = 7028209 | doi-access = free }}</ref> and the hemophagocytic lymphohistiocytosis/macrophage-activation syndrome (i.e. a form of [[Hemophagocytic lymphohistiocytosis]]).<ref name="pmid31723824">{{cite journal | vauthors = Hopfinger G, Jäger U, Worel N | title = CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope | journal = HemaSphere | volume = 3 | issue = 2 | pages = e185 | date = April 2019 | pmid = 31723824 | pmc = 6746029 | doi = 10.1097/HS9.0000000000000185 }}</ref> Individual studies within and outside of this meta-analysis have reported remissions lasting >2 years but also lethal cytokine release syndrome and [[neurotoxicity]] responses to this therapy.<ref name="pmid29808921"/> As a consequence of these studies, the [[European Medicines Agency#Committee for Advanced Therapies|Committee for Advanced Therapies]] and the [[European Medicines Agency#Committee for Medicinal Products for Human Use|Committee for Medicinal Products for Human Use]] of the European Medicines Agency recommend granting marketing authorization for [[tisagenlecleucel]] (i.e. chimeric antigen receptor T cells directed against CD19) in adult patients with DLBCL, NOS who have relapsed after or are refractory to two or more lines of systemic therapy.<ref name="pmid31619548">{{cite journal | vauthors = Ali S, Kjeken R, Niederlaender C, Markey G, Saunders TS, Opsata M, Moltu K, Bremnes B, Grønevik E, Muusse M, Håkonsen GD, Skibeli V, Kalland ME, Wang I, Buajordet I, Urbaniak A, Johnston J, Rantell K, Kerwash E, Schuessler-Lenz M, Salmonson T, Bergh J, Gisselbrecht C, Tzogani K, Papadouli I, Pignatti F | title = The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma | journal = The Oncologist | volume = 25| issue = 2| pages = theoncologist.2019–0233| date = October 2019 | pmid = 31619548 | doi = 10.1634/theoncologist.2019-0233 |pmc=7011647 | doi-access = free }}</ref> The [[European Medicines Agency#Committee for Orphan Medicinal Products|Committee for Orphan Medicinal Products]] of the European Medicines Agency recommends tisagenlecleucel retain its [[orphan drug]] designation.<ref name="pmid31619548"/> The USA [[Food and Drug Administration]] (FDA) has also approved the use of this drug for relapsed or refractory DLBCL of the large B-cell lymphoma subtype in patients who have failed after two or more lines of systemic therapy.<ref name="pmid30413526">{{cite journal | vauthors = Bouchkouj N, Kasamon YL, de Claro RA, George B, Lin X, Lee S, Blumenthal GM, Bryan W, McKee AE, Pazdur R | title = FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-cell Lymphoma | journal = Clinical Cancer Research | volume = 25 | issue = 6 | pages = 1702–1708 | date = March 2019 | pmid = 30413526 | doi = 10.1158/1078-0432.CCR-18-2743 | s2cid = 53249281 | doi-access =  }}</ref> [[Monoclonal antibody therapy|Monoclonal antibodies]] directed against CD19, CD22, CD30, and PD-L1 have been developed for use as immunotherapeutic agents in other hematological malignancies and are being or plan to be tested for their usefulness in DLBCL, NOS.<ref name="pmid29167021"/> In August 2020, the FDA approved the humanized Fc-modified cytolytic CD19 targeting monoclonal antibody [[tafasitamab]] in combination with lenalidomide as a treatment for adult patients with relapsed or refractory DLBCL.<ref>{{cite web |url= https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761163|title= Monjuvi: FDA Approved Drugs |website=US FDA |access-date=August 20, 2020}}</ref> In April 2021, the FDA approved the CD19-directed [[antibody-drug conjugate]] [[loncastuximab tesirine]] as a treatment for adult patients with relapsed or refractory DLBCL after systemic therapy.<ref name="fda">{{cite web|url=https://www.fda.gov/drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma|archive-url=https://web.archive.org/web/20210423201341/https://www.fda.gov/drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma|url-status=dead|archive-date=April 23, 2021|title=FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma|date=11 June 2021|publisher=[[FDA]]|language=en}}</ref>

[[Glofitamab]] (Columvi) is a [[bispecific monoclonal antibody]] that was approved for medical use in Canada in March 2023.<ref>{{cite press release | title=Columvi (Glofitamab for Injection) Receives Health Canada Authorization with Conditions for Adult Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma | publisher=Roche Canada | via=Cision Canada | date=25 March 2023 | url=https://www.newswire.ca/news-releases/columvi-r-glofitamab-for-injection-receives-health-canada-authorization-with-conditions-for-adult-patients-with-relapsed-or-refractory-diffuse-large-b-cell-lymphoma-872796257.html | access-date=24 April 2023}}</ref>

===== Emerging therapies =====
Neoplastic cell expression of CD30 in DLBCL, NOS is a favorable prognostic indicator; in these cases, [[brentuximab vedotin]] may be a useful addition to [[chemotherapy]] treatment protocols. This agent is a CD30-targeting antibody that delivers a toxin, [[monomethyl auristatin E]], to CD30-expressing cells, has therapeutic efficacy against other CD30-expressing lymphomas, and may prove useful in treating the 10–15% of DLBCL, NOS cases expressing this protein. The neoplastic cells in the GBC variant of DLBCL, NOS often have mutations in the ''EZH2, BCL2'' and ''CREBBP'' genes and overactive PI3K/AKT/mTOR and JAK-STAT signaling pathways while neoplastic cells in the ABC variant often have mutations in the ''MYD88, [[CD79A]]'' and ''[[CD79B]]'' ([[polatuzumab vedotin]]) genes and overactive [[B-cell receptor#Signaling pathways of the B-cell receptor|B-cell receptor]], [[Toll-like receptor#Function|toll-like receptor]], and [[NF-κB#Signaling|NF-κB]] signaling pathways.<ref name="pmid29167021"/> These different gene mutations and dysregulated signaling pathways are also being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC cases.<ref name="pmid30859597"/> [[Phosphoinositide 3-kinase inhibitor#Early stage|CUDC-907]], an inhibitor of PI3K and [[histone deacetylase]]s, is being evaluated in two separate clinical trials<ref>{{cite journal|title=Study to Evaluate the Efficacy and Safety of CUDC-907 in Patients With RR DLBCL, Including Patients With MYC Alterations|url=https://clinicaltrials.gov/ct2/show/NCT02674750?term=CUDC-907&cond=Diffuse+Large+B+Cell+Lymphoma&draw=2&rank=1|website=ClinicalTrials.gov|date = 30 August 2019}}</ref><ref>{{cite journal|title=Study to Assess the Safety, Tolerability and Pharmacokinetics of Fimepinostat (CUDC-907) in Patients With Lymphoma|website=ClinicalTrials.gov|date=5 May 2021|url=https://clinicaltrials.gov/ct2/show/NCT01742988?term=CUDC-907&cond=Diffuse+Large+B+Cell+Lymphoma&draw=2&rank=2}}</ref> for the treatment of refractory and/or relapsed DLBCL, NOS including cases with alterations in the ''MYC gene''.<ref name="pmid31735344">{{cite journal | vauthors = Ok CY, Medeiros LJ | title = High-grade B-cell lymphoma: a term re-purposed in the revised WHO classification | journal = Pathology | volume = 52 | issue = 1 | pages = 68–77 | date = January 2020 | pmid = 31735344 | doi = 10.1016/j.pathol.2019.09.008 | s2cid = 208144461 | doi-access =  }}</ref> [[BET inhibitor#Targeting both BD1 and BD2 (bromodomains)|GSK525762]], an inhibitor of [[Bromodomain#Bromo- and Extra-Terminal domain (BET) family|the BET family of proteins]], suppresses expression of the ''MYC'' gene and is undergoing a [[Phases of clinical research|phase I clinical trial]]<ref>{{cite journal|title=Testing a New Anti-cancer Drug Combination, Entinostat and GSK525762C, for Advanced and Refractory Solid Tumors and Lymphomas|url=https://clinicaltrials.gov/ct2/show/NCT03925428?term=GSK525762&draw=2&rank=7|website=ClinicalTrials.gov|date = 25 September 2020}}</ref> for the treatment of high-grade B-cell lymphoma with ''MYC, BL2,'' and/or ''BL6'' rearrangements (i.e. DH/THL). RO6870810, another BET inhibitor, in combination with [[Venetoclax]], an inhibitor of the Bcl-2 protein, is likewise in a phase I clinical trial<ref>{{cite journal|title=A Study to Evaluate Safety, Pharmacokinetics, and Clinical Activity of Combination of RO6870810 and Venetoclax, With or Without Rituximab, in Participants With Relapsed/Refractory DLBCL and/or High-Grade B-Cell Lymphoma and/or High Grade B-Cell Lymphoma With MYC and/or BCL2 and/or BCL6|url=https://clinicaltrials.gov/ct2/show/NCT03255096?term=RO6870810&draw=2&rank=5|website=ClinicalTrials.gov|date = 27 January 2021}}</ref> for the treatment of DH/THL.<ref name="pmid31735344"/> Pharmacological inhibition of BCL-2 is effective in most B cell lymphomas, but often leads to acquired resistance due to the expression of other major anti-apoptotic BCL-2 family proteins like [[Bcl-xL|BCL-XL]] and [[MCL1|MCL-1]].<ref>{{cite journal | vauthors = Zhao X, Ren Y, Lawlor M, Shah BD, Park PM, Lwin T, Wang X, Liu K, Wang M, Gao J, Li T, Xu M, Silva AS, Lee K, Zhang T, Koomen JM, Jiang H, Sudalagunta PR, Meads MB, Cheng F, Bi C, Fu K, Fan H, Dalton WS, Moscinski LC, Shain KH, Sotomayor EM, Wang GG, Gray NS, Cleveland JL, Qi J, Tao J | display-authors = 6 | title = BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models | journal = Cancer Cell | volume = 35 | issue = 5 | pages = 752–766.e9 | date = May 2019 | pmid = 31085176 | pmc = 6945775 | doi = 10.1016/j.ccell.2019.04.005 }}</ref> Combined therapy using MCL-1 inhibitor (S63845) or BCL-XL inhibitor (A-1331852) in addition to Venetoclax can be a solution to overcome this issue.<ref>{{cite journal | vauthors = Dengler MA, Teh CE, Thijssen R, Gangoda L, Lan P, Herold MJ, Gray DH, Kelly GL, Roberts AW, Adams JM | display-authors = 6 | title = Potent efficacy of MCL-1 inhibitor-based therapies in preclinical models of mantle cell lymphoma | journal = Oncogene | volume = 39 | issue = 9 | pages = 2009–2023 | date = February 2020 | pmid = 31772331 | doi = 10.1038/s41388-019-1122-x | s2cid = 208302779 }}</ref>

=== Subtypes of diffuse large B-cell lymphoma ===
DLBCL subtypes have been sorted into groups based on their distinctive morphology or [[Immunophenotyping|immunophenotype]], distinctive clinical issues, and distinctive virus-driven etiology. The prognoses and treatment of these subtypes varies with their severity. Most subtypes are aggressive diseases and consequently treated in a manner similar to DLBCL, NOS. Further details on these subtypes, including their treatments, can be found in their respective main article linkages.{{citation needed|date=April 2022}}

==== DLBCL with a distinctive morphology or immunophenotype ====
===== T cell/histiocyte-rich large B-cell lymphoma =====
{{main|T cell/histiocyte-rich large B-cell lymphoma}}
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a DLBCL in which tumors containing small numbers of usually large neoplastic [[B-cell]]s embedded in a background of reactive [[T-cell]]s and [[histiocyte]]s develop in the liver, spleen, bone marrow and/or, rarely other sites. Patients usually present with advanced disease; their overall 3 year survival rates in different studies range between 46% and 72%.<ref name="pmid31735345"/>

===== ALK+ large B-cell lymphoma =====
{{main|ALK+ large B-cell lymphoma}}
ALK+ large B-cell lymphoma (ALK+ LBCL) is a DLBCL in which neoplastic lymphocytes that express the [[Anaplastic lymphoma kinase|ALK tyrosine kinase receptor]] protein infiltrate [[lymph nodes]] as well as extranodal sites, e.g. the [[mediastinum]], bones, [[bone marrow]], nasopharynx, tongue, stomach, liver, spleen, and skin. About 60% of these individuals present with advanced disease. ALK+ LBCL has an overall 5 year survival rate of ~34%.<ref name="pmid31735345"/>

===== Plasmablastic lymphoma =====
{{main|Plasmablastic lymphoma}}
Plasmablastic lymphoma (PBL) is a DLBCL in which neoplastic [[immunoblast]]ic or [[Plasma cell|plasmablastic]] cells embedded in a background of other cell types infiltrate the oral/nasal cavity or much less often the gastrointestinal tract.<ref name="pmid31735345"/> Some 70% of individuals with PBL are infected with EBV<ref name="pmid29885408">{{cite journal | vauthors = Rezk SA, Zhao X, Weiss LM | title = Epstein—Barr virus-associated lymphoid proliferations, a 2018 update | journal = Human Pathology | volume = 79| pages = 18–41| date = June 2018 | pmid = 29885408 | doi = 10.1016/j.humpath.2018.05.020 | s2cid = 47010934 }}</ref> and/or (particularly those with oral/nasal cavity disease) [[HIV|human immunodeficiency virus]] (HIV).<ref name="pmid31735345"/> PBL is an aggressive disease with a median survival time of ~15 months.<ref name="pmid31735345"/>

===== Intravascular large B-cell lymphoma =====
{{main|Intravascular large B-cell lymphoma}}
Intravascular large B-cell lymphoma (IVLBCL) is a DLBCL in which medium- to large-sized neoplastic B-cells infiltrate small- to medium-sized blood vessels and [[Capillary#Sinusoidal|sinusoids]] in the liver, spleen, and/or bone marrow. IVLBCL may be associated with the [[Hemophagocytic lymphohistiocytosis|hemophagic syndrome]] (i.e. excessive [[cytokine storm|cytokine secretion]] and systemic inflammation). Patients with the latter syndrome have very short survival times.<ref name="pmid31735345"/> The poor prognosis of this disease has been significantly improved by [[rituximab]] or similar immunochemotherapy drugs but significant proportions of these responding cases relapse, often with central nervous system involvement.<ref name="pmid30111607">{{cite journal | vauthors = Ponzoni M, Campo E, Nakamura S | title = Intravascular large B-cell lymphoma: a chameleon with multiple faces and many masks | journal = Blood | volume = 132 | issue = 15 | pages = 1561–1567 | date = October 2018 | pmid = 30111607 | doi = 10.1182/blood-2017-04-737445 | doi-access = free }}</ref>

===== Large B-cell lymphoma with IRF4 rearrangement =====
{{main|IRF4}}
Large B-cell lymphoma with IRF4 rearrangement (LBCL with IRF4 rearrangement) is a DLBCL in which tissue infiltrates containing intermediate- or large-sized neoplastic B-cells strongly express a [[chromosomal translocation]] involving the ''[[IRF4]]'' gene on the [[Locus (genetics)|short arm]] of chromosome 6. These cells form [[Follicle (anatomy)|follicular]], follicular and diffuse, or entirely diffuse infiltrates<ref name="pmid31735345"/> in [[Waldeyer's tonsillar ring]] or other regions of the head and neck. The disease, which represents ~0.05% of all DLBCL, occurs primarily in children and young adults and typically has a good prognoses.<ref name="pmid30380402"/> Cases with a follicular pattern of tissue infiltrates often have indolent disease and an excellent prognosis following excision and may not need chemotherapy. Cases with a purely diffuse tissue infiltrate pattern, in contrast, often do require chemotherapy.<ref name="pmid31735345"/>

==== DLBCL with distinctive clinical issues ====
===== Primary mediastinal large B-cell lymphoma =====
{{main|Primary mediastinal large B-cell lymphoma}}
Primary mediastinal large B-cell lymphoma (PMBL), also termed primary mediastinal (thymic) large B-cell lymphoma, is a DLBCL in which neoplastic B-cells infiltrates are commonly located in [[Sclerosis (medicine)|sclerotic]]/fibrous tissues of the [[thymus]] and [[mediastinal]] lymph nodes. The disease represents 6–10% of all DLBCL cases, presents with early stage disease in ~80% of cases, and has an overall survival rate at 5 years of 75–85%.<ref name="pmid31735345"/>

===== Primary cutaneous diffuse large B-cell lymphoma, leg type =====
{{main|Primary cutaneous diffuse large B-cell lymphoma, leg type}}
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a DLBCL in which diffuse patterns of immunoblastic and/or [[centroblast]]ic B-cells infiltrate the [[dermis]] and/or subcutaneous tissue principally, but not exclusively, of the legs. This disease's 5-year overall survival rate is 50–60%.<ref name="pmid31735345"/>

===== Primary diffuse large B-cell lymphoma of the central nervous system =====
{{main|Primary central nervous system lymphoma}}
Primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS, also termed primary central nervous system lymphoma [PCNSL]) is a DLBCL in which diffuse patterns of neoplastic B-cells with centroblastic, immunoblastic, or poorly [[Cellular differentiation|differentiated]] features infiltrate the brain, spinal cord, [[leptomeninges]], or eye.<ref name="pmid30380402"/> The disease usually presents as a single lesion with a predilection for the [[supratentorial region]] of the brain but may involve the eye in 15–25% of cases, the [[cerebrospinal fluid]] in 7–42% of cases, and the spinal cord in ~1% of cases. The disease has a 5-year overall survival rate of ~30%.<ref name="pmid31735345"/>

===== Diffuse large B-cell lymphoma associated with chronic inflammation =====
{{main|Diffuse large B-cell lymphoma associated with chronic inflammation|Fibrin-associated diffuse large B-cell lymphoma}}
Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is an [[Epstein–Barr virus-associated lymphoproliferative diseases#Epstein–Barr virus-associated diffuse large B cell lymphoma associated with chronic inflammation|Epstein–Barr virus-associated lymphoproliferative disease]] arising in persons with a long and persistent history of chronic inflammation. The disease's lesions consist of large, mature-appearing B-cells infiltrating the lung's [[pleura]] and nearby tissues. Most cases have occurred in patients who were given a [[pneumothorax]] (i.e. therapeutic introduction of air into the chest cavity in order to collapse and thereby "rest" the lung) to treat [[pulmonary tuberculosis]] that had progressed to a [[Pleural empyema|pyothorax]] (i.e. [[pus]] in the [[pleural cavity]]). '''Fibrin-associated large B-cell lymphoma''' (FA-DLBCL), often considered a sub-type of DLBCL-CI, is an infiltration of large neoplastic B-cells and [[fibrin]] affix to a prosthesis (e.g., cardiac valve, orthopaedic device) or accumulate within a [[hydrocele]], [[pseudocyst]], [[cardiac myxoma]], or chronic [[subdural hematoma]]. The B-cells in these lesions are often but not always infected with the Epstein–Barr virus.<ref name="pmid31735345"/> DLBCL-CI occurring in cases of pleural empyema (sometimes termed '''pyothorax-associated lymphoma''', i.e. PAL) is an aggressive lymphoma with a five-year overall survival rate of 20–35%; FA-DLBCL, when involving the heart (e.g. occurring on myxomata or prosthetic valves) or vasculature structures (e.g. on thrombus-laden vascular grafts), may involve life-threatening cardiovascular complications, particularly strokes. Outside of these complications, however, DLBCL-CI usually has a highly favorable outcome.<ref name="pmid30380402"/>

===== Lymphomatoid granulomatosis =====
{{main|Lymphomatoid granulomatosis}}
Lymphomatoid granulomatosis (LYG) is a DLBCL in which large, atypical B-cells with immunoblastic or [[Hodgkin disease]]-like features that are infected by the [[Epstein-Barr virus]] center around and destroy the [[microvasculature]]. Lymphomatoid granulomatosis almost always involves the lung but may concurrently involve the brain, peripheral nervous system, skin, kidneys, liver, gastrointestinal tract, and/or upper respiratory tract; LYG has an increased incidence in persons with [[Wiskott–Aldrich syndrome]] or [[HIV]] or who are immunosuppression due to [[chemotherapy]] or organ transplantation.<ref name="pmid31735345"/> The disease's prognosis is highly variable: patients with low grade disease often require no therapy except [[watchful waiting]] while patients with high grade disease usually require chemotherapy.<ref name="pmid27521314">{{cite journal | vauthors = Chavez JC, Sandoval-Sus J, Horna P, Dalia S, Bello C, Chevernick P, Sotomayor EM, Sokol L, Shah B | title = Lymphomatoid Granulomatosis: A Single Institution Experience and Review of the Literature | journal = Clinical Lymphoma, Myeloma & Leukemia | volume = 16 | issue = Suppl | pages = S170–4 | date = August 2016 | pmid = 27521314 | doi = 10.1016/j.clml.2016.02.024 }}</ref>

===== Primary effusion lymphoma =====
{{main|Primary effusion lymphoma}} 
Primary effusion lymphoma (PEL) is a DLBCL in which neoplastic B cells that resemble immunoblasts, plasmablasts, or [[Reed–Sternberg cell]]s infiltrate the [[Pulmonary pleurae|pleural]], [[Pericardium|pericardial]], or [[Peritoneum|peritoneal]] membranes that surround the lungs, heart, and abdominal organs, respectively. This infiltration leads to the seeping of fluid into the cavities which are encased by these membranes, i.e. it leads to [[pleural effusion]]s, [[pericardial effusion]]s, and abdominal [[ascites]]. Some cases of PEL also involve the [[gastrointestinal tract]] and lymph nodes. The disease occurs primarily in people who are immunosuppressed or test positive for [[HIV]]<ref name="pmid31735345"/> and are also [[Infection#Subclinical versus clinical (latent versus apparent)|latently infected]] with [[Kaposi's sarcoma-associated herpesvirus]];<ref name="pmid30154110" /> PEL is an aggressive disease with an overall 1 year survival rate of ~30%.<ref name="pmid30154110"/>

==== DLBCL driven by viruses ====
===== Epstein–Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified =====
{{main|Epstein–Barr virus-associated lymphoproliferative diseases#Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified}}
Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS) is a B-cell lymphoma in which neoplastic B-cells that are infected with the Epstein-Barr virus cause a disease that does not fit into other subtypes of DLBCL. In EBV+ DLBCL, small neoplastic B-cells, other lymphocyte types, plasma cells, histiocytes and epithelioid cells interspersed with Reed–Sternberg-like cells<ref name="pmid30380402"/> infiltrate, almost exclusively, lymph nodes.<ref name="pmid25999451" /> Elderly patients with the disease have median survival times of ~2 years while young patients have long-term treatment-related remissions in >80% of cases.<ref name="pmid30380402"/>

===== HHV8-positive diffuse large B-cell lymphoma, NOS =====
{{further|HHV-8-associated MCD}}
[[HHV8-positive diffuse large B-cell lymphoma]], NOS (HHV8+ DLBCL, NOS; also termed HHV8-positive diffuse large B-cell lymphoma [HHV8+ DLBCL]) is a DLBCL in which [[Kaposi's sarcoma-associated herpesvirus]]-infected, medium- to large-size neoplastic B-cells that resemble lymphocytes or immunoblasts infiltrate lymph nodes (~80% of cases) and, when disseminated (20% of cases), the liver and spleen. This infiltration usually disrupts the normal architecture of the involved tissues. HHV8+ DLBCL develops in [[HIV]]-infected individuals in ~50% of cases, in individuals with [[Castleman disease#Human herpesvirus 8 associated multicentric Castleman disease|multicentric Castleman disease, plasma cell variant]] in uncommon cases, and in individuals with [[Kaposi sarcoma]] in rare cases. HHV8+ DLBCL commonly takes an aggressive course and has a poor prognosis.<ref name="pmid31735345"/>

== Related disorders ==
=== ''Helicobactor pylori'' associated diffuse large B-cell lymphoma ===
{{See also|Helicobacter pylori#Diffuse large B-cell lymphoma}}
Rare cases of DLBCL are associated with the presence of the bacterium, ''Helicobacter pylori'', in the neoplastic B-cells.<ref name="pmid28288708"/> While the histology of ''Helicobactor pylori''-associated diffuse large B-cell lymphoma (''H. pylori''+ DLBCL) is typical of DLBCL, the disease is sometimes a progression of [[mantle cell lymphoma]], is often restricted to the stomach, is less aggressive that most DLBCL cases, and may respond to a drug regimen consisting of [[antibiotic]]s and [[proton pump inhibitor]]s directed at killing the bacterium.<ref name="pmid24949857">{{cite journal | vauthors = Kuo SH, Yeh KH, Chen LT, Lin CW, Hsu PN, Hsu C, Wu MS, Tzeng YS, Tsai HJ, Wang HP, Cheng AL | title = Helicobacter pylori-related diffuse large B-cell lymphoma of the stomach: a distinct entity with lower aggressiveness and higher chemosensitivity | journal = Blood Cancer Journal | volume = 4 | issue = 6| pages = e220 | date = June 2014 | pmid = 24949857 | pmc = 4080211 | doi = 10.1038/bcj.2014.40 }}</ref><ref name="pmid31455250" /> Perhaps because of these features of the disease, ''H. pylori''+ DLBCL has not been classified as a DLBCL by the World Health Organization, 2016.<ref name="pmid31455250"/>

Recent studies suggest that localized, early-stage ''H. pylori''+ DLBCL, when limited to the stomach, is successfully treated with [[Helicobacter pylori eradication protocols|''H. pylori eradication protocols'']] consisting of two or more antibiotics plus a proton pump inhibitor.<ref name="pmid25852262">{{cite journal | vauthors = Paydas S | title = Helicobacter pylori eradication in gastric diffuse large B cell lymphoma | journal = World Journal of Gastroenterology | volume = 21 | issue = 13 | pages = 3773–6 | date = April 2015 | pmid = 25852262 | pmc = 4385524 | doi = 10.3748/wjg.v21.i13.3773 | doi-access = free }}</ref><ref name="pmid24949857"/><ref name="pmid31727764">{{cite journal | vauthors = Tsai HJ, Tai JJ, Chen LT, Wu MS, Yeh KH, Lin CW, Wang TE, Wang HP, Yu FJ, Liou JM, Hsiao CF, Cheng TY, Yeh HJ, Ko CW, Chen MJ, Lo GH, Hsu PI, Chang CS, Hwang WS, Chuang SS, Lee HW, Shun CT, Chiu CF, Wang WM, Hsieh CY, Liu TW, Lin JT, Kuo SH, Cheng AL | title = A multicenter prospective study of first-line antibiotic therapy for early-stage gastric mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma with histological evidence of mucosa-associated lymphoid tissue | journal = Haematologica | volume = 105| issue = 7| pages = e349–e354| date = November 2019 | pmid = 31727764 | doi = 10.3324/haematol.2019.228775 | pmc = 7327622 | doi-access = free }}</ref><ref name="pmid31455250"/> However, these studies also agree that patients treated with one of these ''H. pylori'' eradication regimes need to be carefully followed: those unresponsive to, or worsening on, these regimens should be switched to a chemotherapy regimen (e.g. R-CHOP) and/or, for complicated bulky disease, surgery and/or local radiotherapy.<ref name="pmid24949857"/><ref name="pmid31455250"/>

=== Epstein–Barr virus-positive mucocutaneous ulcer ===
{{main|Mouth ulcer|Epstein–Barr virus-associated lymphoproliferative diseases#Epstein–Barr virus-positive mucocutaneous ulcer}}
Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in which Epstein–Barr virus-infected B-cells proliferate and cause [[ulceration]]s in the [[mucous membranes]] and skin of [[Immunosuppression|immunosuppressed]] individuals. Its lesions consist of Epstein–Barr virus-positive, variable-sized, atypical B-cells that by conventional histopathologic criteria indicate the lesions are a form of DLBCL. Since these lesions regress spontaneously without anti-cancer treatment, EBVMCU is now considered a pseudo-malignant disorder.<ref name="pmid31257347">{{cite journal | vauthors = Ikeda T, Gion Y, Yoshino T, Sato Y | title = A review of EBV-positive mucocutaneous ulcers focusing on clinical and pathological aspects | journal = Journal of Clinical and Experimental Hematopathology | volume = 59 | issue = 2 | pages = 64–71 | date = 2019 | pmid = 31257347 | pmc = 6661964 | doi = 10.3960/jslrt.18039 }}</ref> Elderly individuals that evidence the disease but have no other cause for immunosuppression may exhibit a relapsing and remitting course with their ulcers worsening but then regressing spontaneously.<ref name="pmid28477890">{{cite journal | vauthors = Goodlad JR | title = Epstein–Barr Virus-associated Lymphoproliferative Disorders in the Skin | journal = Surgical Pathology Clinics | volume = 10 | issue = 2 | pages = 429–453 | date = June 2017 | pmid = 28477890 | doi = 10.1016/j.path.2017.01.001 }}</ref> Persistent and/or severely symptomatic cases have had excellent responses to [[rituximab]].<ref name="pmid29518976">{{cite journal | vauthors = Dojcinov SD, Fend F, Quintanilla-Martinez L | title = EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts | journal = Pathogens (Basel, Switzerland) | volume = 7 | issue = 1 | pages = 28| date = March 2018 | pmid = 29518976 | pmc = 5874754 | doi = 10.3390/pathogens7010028 | doi-access = free }}</ref> Individuals developing these ulcers as a consequence of immunosuppressive therapy generally have a remission after the dosage of the drugs used in their immunosuppressive treatments are reduced. Most of these patients do not relapse.<ref name="pmid28477890"/>

==Notable cases==
*[[Mark Hoppus]], musician and co-lead singer of [[Blink 182]]<ref>{{cite web | url=https://www.nytimes.com/2025/04/03/arts/music/mark-hoppus-blink-182-fahrenheit-182-memoir.html | title=What's His Age Again? Blink-182's Mark Hoppus (Now 53) Looks Back | work=The New York Times | date=3 April 2025 | last1=Yarm | first1=Mark | last2=Schell | first2=Adali }}</ref>
== See also ==
*[[Germinal center B-cell like diffuse large B-cell lymphoma]]

== References ==
{{Reflist|refs=

<ref name=Akyurek2011>{{cite journal | vauthors = Akyurek N, Uner A, Benekli M, Barista I | 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 | journal = Cancer | volume = 118 | issue = 17 | pages = 4173–4183 | date = September 2012 | pmid = 22213394 | doi = 10.1002/cncr.27396 | s2cid = 19134744 | doi-access = free }}</ref>

<ref name=Morton2006>{{cite journal | vauthors = Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS | title = Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001 | journal = Blood | volume = 107 | issue = 1 | pages = 265–276 | date = January 2006 | pmid = 16150940 | pmc = 1895348 | doi = 10.1182/blood-2005-06-2508 }}</ref>

<ref name=Alizadeh2000>{{cite journal | vauthors = Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM | display-authors = 6 | title = Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling | journal = Nature | volume = 403 | issue = 6769 | pages = 503–511 | date = February 2000 | pmid = 10676951 | doi = 10.1038/35000501 | s2cid = 4382833 | bibcode = 2000Natur.403..503A }}</ref>

<ref name=Blood1997>{{cite journal | vauthors = | title = A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project | journal = Blood | volume = 89 | issue = 11 | pages = 3909–3918 | date = June 1997 | pmid = 9166827 | doi = 10.1182/blood.V89.11.3909 | doi-access = free }}</ref>

<ref name=Feugier2005>{{cite journal | vauthors = Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B | display-authors = 6 | title = Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte | journal = Journal of Clinical Oncology | volume = 23 | issue = 18 | pages = 4117–4126 | date = June 2005 | pmid = 15867204 | doi = 10.1200/JCO.2005.09.131 | s2cid = 23556248 | doi-access = free }}</ref>

<<ref name=Kumar2009>{{cite book| vauthors = Kumar V, Abbas AK, Fausto N, Aster JC |title=Robbins & Cotran Pathologic Basis of Disease|date=28 May 2009|publisher=Elsevier Health Sciences|isbn=978-1-4377-2015-0|page=607}}</ref>

<ref name=Smith2010>{{cite journal | vauthors = Smith A, Roman E, Howell D, Jones R, Patmore R, Jack A | title = The Haematological Malignancy Research Network (HMRN): a new information strategy for population based epidemiology and health service research | journal = British Journal of Haematology | volume = 148 | issue = 5 | pages = 739–753 | date = March 2010 | pmid = 19958356 | pmc = 3066245 | doi = 10.1111/j.1365-2141.2009.08010.x | author7 = Haematological Malignancy Research Network }}</ref>

<ref name=Smith2011>{{cite journal | vauthors = Smith A, Howell D, Patmore R, Jack A, Roman E | title = Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network | journal = British Journal of Cancer | volume = 105 | issue = 11 | pages = 1684–1692 | date = November 2011 | pmid = 22045184 | pmc = 3242607 | doi = 10.1038/bjc.2011.450 }}</ref>

<ref name=UpToDateEpi2012>{{cite book| vauthors = Freeman AS, Aster JS | veditors = Basow DS |title=UpToDate|year=2012|publisher=UpToDate|location=Waltham, MA|chapter=Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma|chapter-url=http://www.uptodate.com/contents/epidemiology-clinical-manifestations-pathologic-features-and-diagnosis-of-diffuse-large-b-cell-lymphoma}}</ref>
}}

== Sources ==
* {{cite book|title=WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues| veditors = Swerdlow SH, Campo E, Jaffe ES, Pileri SA |year=2008 |publisher=IARC |location=Lyon|isbn=978-92-832-2431-0}}
* {{cite book| vauthors = Goldman L, Schafer AI |title=Goldman's Cecil Medicine|edition=24th|year=2012|isbn=978-1-4377-1604-7|url=http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-1604-7..00191-3&isbn=978-1-4377-1604-7}}
* {{cite book| vauthors = Turgeon ML |title=Clinical hematology: theory and procedures|url=https://archive.org/details/clinicalhematolo0004turg|url-access=registration|publisher=Lippincott Williams & Wilkins|location=Hagerstown, MD|year=2005|isbn=978-0-7817-5007-3}}

== External links ==
{{Medical resources
| DiseasesDB =
| ICD10 = {{ICD10|C|83|3}}
| ICD9 =
| ICDO = {{ICDO|9680|3}}
| OMIM =
| MedlinePlus =
| eMedicineSubj = article
| eMedicineTopic = 202969
| MeshID = D016403
}}
{{Lymphoid malignancy}}
{{Chromosomal abnormalities}}

[[Category:Lymphoma]]
[[Category:Non-Hodgkin lymphoma]]
[[Category:Epstein–Barr virus–associated diseases]]