Fact-checked by Grok 2 weeks ago

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, comprising about 30% of all newly diagnosed cases in the United States.^[1] It represents an aggressive, fast-growing cancer that arises from B lymphocytes, a type of white blood cell in the immune system, and typically forms rapidly expanding tumors in the lymph nodes, spleen, liver, bone marrow, or extranodal sites such as the gastrointestinal tract, skin, or central nervous system.^[2]^[3] While the exact cause remains unclear, it often results from genetic mutations in B cells leading to uncontrolled proliferation, and it can sometimes transform from indolent lymphomas like follicular lymphoma.^[3] Common symptoms of DLBCL include painless swelling of lymph nodes in the neck, armpits, or groin, as well as B symptoms such as unexplained fever, drenching night sweats, and unintentional weight loss exceeding 10% of body weight over six months.^[2]^[3] Depending on the tumor's location, additional manifestations may involve abdominal pain, nausea, vomiting from gastrointestinal involvement; headaches, confusion, or vision changes if the central nervous system is affected; or fatigue and itching from widespread disease.^[3] Risk factors for developing DLBCL include advancing age, with most cases occurring in individuals over 60 years old, though it can affect any age group.^[3] A weakened immune system—due to conditions like HIV/AIDS, organ transplants requiring immunosuppressive drugs, or autoimmune disorders such as rheumatoid arthritis—increases susceptibility, as do certain infections including Epstein-Barr virus and Helicobacter pylori.^[2]^[3] Family history of lymphoma and exposure to chemicals like pesticides may also elevate risk, though most cases arise sporadically without identifiable triggers.^[3] Diagnosis typically involves biopsy of an affected lymph node or tissue, confirmed by histopathological examination showing large B-cell proliferation, often with immunohistochemical markers like CD20 positivity.^[2] Staging uses the Lugano classification, incorporating imaging such as PET-CT scans, bone marrow biopsy, and sometimes cerebrospinal fluid analysis for central nervous system involvement.^[1] Standard treatment for limited-stage (I/II) disease is usually four to six cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), potentially followed by involved-site radiation therapy, achieving cure rates up to 90%.^[1] For advanced-stage (III/IV) or high-risk cases, six cycles of R-CHOP or the regimen Pola-R-CHP (polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone) is standard, with options like autologous stem cell transplant for relapsed disease or CAR-T cell therapy such as axicabtagene ciloleucel for refractory cases.^[1] Prognosis varies by the NCCN International Prognostic Index (NCCN-IPI; factors: age, stage, performance status, lactate dehydrogenase levels, extranodal sites), with five-year overall survival ranging from 96% in low-risk patients to 33% in high-risk ones.^[1] Molecular subtypes, such as germinal center B-cell-like (GCB) and activated B-cell-like (ABC), influence outcomes and treatment response, with ABC subtypes generally faring worse but benefiting more from targeted therapies like polatuzumab vedotin.^[1] Ongoing clinical trials explore novel immunotherapies and combinations to improve cure rates, particularly for relapsed or double-hit lymphomas involving MYC and BCL2 rearrangements.^[1]

Overview

Definition and classification

Diffuse large B-cell lymphoma (DLBCL) is an aggressive neoplasm of mature B cells characterized by the diffuse proliferation of large lymphoid cells with a diameter equal to or larger than that of normal macrophage nuclei, often exhibiting a starry-sky pattern due to interspersed tingible body macrophages. It represents the most common subtype of non-Hodgkin lymphoma, accounting for approximately 25-30% of all cases in adults.^[4]^[5] The classification of DLBCL has evolved through several landmark systems. The Rappaport classification, first proposed in 1956 and revised in 1966, relied primarily on histologic patterns to categorize lymphomas into nodular or diffuse types, grouping what is now DLBCL under diffuse histiocytic lymphoma without immunophenotypic distinction.^[6] This morphology-based approach was later refined in the Revised European-American Lymphoma (REAL) classification of 1994, which introduced DLBCL as a distinct entity within B-cell neoplasms, incorporating immunophenotypic, genetic, and clinical features to better reflect biologic heterogeneity.^[7] Subsequent World Health Organization (WHO) classifications, beginning with the 2001 edition and updated in 2008, 2016, and most recently in 2022, have integrated these advances, positioning DLBCL within the category of mature B-cell neoplasms while emphasizing its clinical and molecular diversity.^[8] In the 5th edition of the WHO Classification of Haematolymphoid Tumours (2022), DLBCL is recognized as a heterogeneous group, with the prototypic form designated as DLBCL, not otherwise specified (NOS), defined by its aggressive behavior, diffuse architecture, and large-cell morphology without assignment to more specific subtypes like primary mediastinal or intravascular large B-cell lymphoma.^[8] A key aspect of this classification is cell-of-origin (COO) subtyping, which stratifies DLBCL into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes based on gene expression profiling that recapitulates the normal stages of B-cell development.^[9] The Hans algorithm serves as a practical immunohistochemical surrogate for COO determination, utilizing antibodies against CD10, BCL6, and MUM1/IRF4 to classify cases with approximately 80% concordance to gene expression methods, aiding in prognostic and therapeutic stratification.^[10] Immunophenotypically, DLBCL, NOS typically expresses pan-B-cell markers such as CD19, CD20, CD22, CD79a, and PAX5, confirming its B-cell lineage, while surface immunoglobulin expression is often weak or absent.^[11] BCL6 is frequently positive (60-90% of cases), reflecting germinal center association in GCB subtypes, whereas BCL2 expression is more common in ABC subtypes (variable across 20-90%), and Ki-67 proliferation index is usually high (>40%).^[11]^[12]

Epidemiology

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 30-40% of all NHL cases worldwide. The global age-standardized incidence rate of DLBCL ranges from approximately 2 to 4 cases per 100,000 person-years, though this varies significantly by region and population, with overall NHL incidence at 5.6 per 100,000 in 2022 according to GLOBOCAN data. Incidence increases sharply with age, peaking in the 60-70 age group, and is less common in children under 15 years, comprising 10-20% of pediatric non-Hodgkin lymphomas. In the United States, the age-adjusted incidence is 5.6 per 100,000 (2018-2022 Surveillance, Epidemiology, and End Results (SEER) program data). Demographic patterns show a male predominance, with a male-to-female ratio of approximately 1.5:1, reflected in U.S. rates of 6.7 per 100,000 for males versus 4.6 per 100,000 for females (2018-2022). Ethnic variations are notable, with higher incidence among non-Hispanic whites (9.2 per 100,000 in the U.S., 2018-2022). DLBCL is strongly associated with immunosuppression; in people with HIV, the risk is elevated 10- to 100-fold depending on CD4 count, making DLBCL the most common NHL subtype in this population. Similarly, solid organ transplant recipients face a 12-fold increased risk of posttransplant lymphoproliferative disorder manifesting as DLBCL due to iatrogenic immunosuppression. Geographic distribution reveals higher rates in developed regions, with 5-7 cases per 100,000 in North America and Western Europe, compared to 1-2 per 100,000 in Asia and sub-Saharan Africa. Worldwide incidence ranges from 2.3 to 13.8 per 100,000 person-years, influenced by diagnostic capabilities and HIV prevalence.^[13] Temporal trends indicate an increase in DLBCL incidence since the 1970s, paralleling rises in NHL overall at 3-4% annually, attributed to improved diagnostics and an aging population. From 2020 to 2025, projections show varying trends in high-income countries; an 11% rise in incident cases in the U.S., while recent data in Australia indicate a 6.4% annual decline in males (2021-2023), with incidence stabilizing or slightly declining in some regions. Prevalence has grown, with U.S. 20-year prevalence increasing 14% over this period.^[14]^[15]

Clinical presentation

Signs and symptoms

Diffuse large B-cell lymphoma (DLBCL) most commonly presents with painless lymphadenopathy, affecting approximately 60-70% of patients, typically involving cervical, axillary, or inguinal lymph nodes that enlarge rapidly and may form palpable masses.^[16]^[3] These swellings are often the initial sign prompting medical evaluation, though they can occasionally cause discomfort if compressing nearby structures.^[4] Systemic B symptoms, including unexplained fever above 38°C, drenching night sweats, and unintentional weight loss exceeding 10% of body weight over six months, occur in 30-40% of cases and indicate more advanced disease.^[4]^[17] These symptoms reflect the lymphoma's aggressive nature and cytokine-mediated effects, often accompanying widespread nodal involvement.^[18] Extranodal involvement is seen in about 40% of patients at diagnosis, with the gastrointestinal tract (particularly the stomach), central nervous system, and bone being frequent sites.^[19] Gastrointestinal disease may cause abdominal pain, swelling, nausea, or bleeding, while central nervous system involvement can lead to headaches, neurological deficits such as confusion or seizures, and focal weaknesses.^[3] Bone lesions typically present with localized pain and increased fracture risk, and cutaneous involvement may manifest as skin lesions or rashes.^[3]^[4] Paraneoplastic phenomena are rare in DLBCL but can include autoimmune hemolytic anemia, where immune-mediated red blood cell destruction leads to fatigue and jaundice prior to lymphoma diagnosis.^[20]^[21]

Risk factors

Advanced age is the strongest non-modifiable risk factor for diffuse large B-cell lymphoma (DLBCL), with incidence rates increasing significantly after 60 years, accounting for the majority of cases in older adults.^[3]^[22] Male sex is also associated with higher risk, with males comprising approximately 56% of cases and showing elevated incidence compared to females across most age groups.^[23] Family history of lymphoma or hematologic malignancies confers a modest but established increased risk, observed in about 5% of DLBCL cases with familial clustering, particularly among first-degree relatives where the relative risk can reach 2- to 10-fold depending on the specific subtype history.^[24]^[25] Immunosuppression substantially elevates DLBCL susceptibility through impaired immune surveillance and chronic B-cell stimulation. Human immunodeficiency virus (HIV) infection increases the risk by 20- to 80-fold, particularly in cases of profound CD4+ T-cell depletion and uncontrolled viremia, making DLBCL the most common non-Hodgkin lymphoma subtype in people with HIV.^[26]^[27] Post-organ transplantation, iatrogenic immunosuppression leads to posttransplant lymphoproliferative disorders, with DLBCL comprising up to 60% of these cases and a standardized incidence ratio exceeding 17-fold compared to the general population.^[28] Autoimmune diseases, such as Sjögren's syndrome and rheumatoid arthritis, are linked to a 4- to 8-fold higher risk due to chronic inflammation and B-cell hyperactivity, with Sjögren's showing particularly strong associations in Mendelian randomization studies.^[29]^[30] Certain infections are associated with increased DLBCL risk. Epstein-Barr virus (EBV) is linked to approximately 10% of DLBCL cases, particularly in elderly immunocompetent patients and in immunosuppression contexts.^[4] Helicobacter pylori infection is a risk factor for gastric DLBCL, often through progression from mucosa-associated lymphoid tissue lymphoma.^[3] Environmental exposures contribute to DLBCL risk, though evidence varies by agent. Occupational or prolonged exposure to pesticides, including insecticides and herbicides, is associated with a 1.5- to 3-fold increased risk, likely through genotoxic and immunotoxic mechanisms affecting lymphoid cells.^[22]^[31] Obesity, defined as a body mass index greater than 30 kg/m², correlates with approximately a 1.5-fold elevated risk for DLBCL, potentially mediated by adipose tissue-derived inflammation and altered immune function.^[32]^[33] Emerging research as of 2025 highlights microbiome dysbiosis and chronic inflammation as potential risk modifiers. Gut microbiota alterations, characterized by depletion of beneficial taxa like Bifidobacterium and enrichment of pro-inflammatory species, are observed in DLBCL patients and may promote lymphomagenesis through enhanced systemic inflammation and immune dysregulation, with Mendelian randomization supporting causal links for specific microbial genera.^[34]^[35] Chronic low-grade inflammation from these factors could synergize with established risks, though prospective studies are needed to clarify their independent contributions.^[36]

Pathogenesis

Pathophysiology

Diffuse large B-cell lymphoma (DLBCL) originates from the malignant transformation of B-cells, predominantly those at the germinal center or post-germinal center stages of differentiation within lymphoid tissues.^[4] This transformation leads to aggressive proliferation characterized by rapid cell division and evasion of programmed cell death (apoptosis), often through overexpression of anti-apoptotic proteins such as BCL2 in over 80% of cases.^[4] The resulting neoplastic B-cells exhibit dysregulated growth, forming large, diffuse masses that disrupt normal lymph node architecture and can infiltrate extranodal sites.^[4] The tumor microenvironment plays a critical role in sustaining DLBCL progression by fostering interactions between malignant B-cells and non-malignant immune cells. Tumor-associated macrophages, particularly pro-tumorigenic M2-polarized subsets, and regulatory T-cells infiltrate the lymphoma niche, promoting B-cell survival through secretion of cytokines such as interleukin-6 (IL-6), which is especially prominent in the activated B-cell (ABC) subtype.^[37]^[38] These cytokines enhance tumor cell proliferation, suppress anti-tumor immunity, and drive chronic inflammation, contributing to disease aggressiveness.^[39] DLBCL can arise de novo or progress from indolent precursors, with transformation from follicular lymphoma occurring at an annual rate of approximately 2-3%, leading to a more aggressive phenotype.^[40] This progression is facilitated by the tumor cells' ability to exhibit extranodal tropism, mediated by adhesion molecules and homing receptors such as α4β7 integrin, which direct lymphoma cells to specific tissues like the gastrointestinal tract or central nervous system.^[41] Key signaling pathways underpin these dynamics: constitutive NF-κB activation, a hallmark of the ABC subtype, promotes survival and inflammation, while the PI3K/AKT pathway is dysregulated in both ABC and germinal center B-cell (GCB) subtypes to enhance proliferation and metabolic demands.^[42]^[43] Recent insights from 2024-2025 studies highlight metabolic reprogramming as a driver of DLBCL pathogenesis, with upregulation of glycolysis supporting rapid energy needs and biosynthetic processes in tumor cells.^[44] This shift, influenced by microenvironmental cues like IL-6, enables adaptation to hypoxic conditions and resistance to therapies, further exacerbating disease progression.^[45]

Genetic and molecular features

Diffuse large B-cell lymphoma (DLBCL) exhibits a complex genomic landscape characterized by recurrent somatic mutations, chromosomal translocations, and copy number alterations that drive oncogenesis and influence clinical behavior. Whole-genome sequencing and targeted next-generation sequencing studies have identified hundreds of mutated genes, with alterations affecting key pathways such as B-cell receptor signaling, epigenetic regulation, and apoptosis. These genetic features contribute to the heterogeneity of DLBCL and underpin its classification into molecular subtypes.^[46]^[47] Recurrent genetic alterations in DLBCL include mutations in the tumor suppressor TP53, occurring in approximately 22% of cases, which are associated with impaired DNA repair and poor prognosis, including reduced overall and progression-free survival in patients treated with R-CHOP. Chromosomal translocations involving MYC, BCL2, and BCL6 are also common, with double-hit (involving two of these genes) or triple-hit lymphomas comprising 5-10% of cases and conferring an aggressive phenotype with inferior outcomes. BCL6 translocations, present in 30-40% of DLBCL, disrupt transcriptional regulation and are enriched in germinal center B-cell-like (GCB) subtypes, while BCL2 translocations occur in 15-20% overall and up to 30-40% of GCB-DLBCL. MYC rearrangements are seen in 5-14% of GCB-DLBCL cases.^[48]^[49]^[47] Subtype-specific mutations further delineate DLBCL biology. In activated B-cell-like (ABC) DLBCL, which accounts for about 30% of cases, mutations in CD79B (activating B-cell receptor signaling) and MYD88 (activating NF-κB via Toll-like receptor signaling) are prevalent, occurring in approximately 20-25% and 25-30% of ABC tumors, respectively, often co-occurring to promote chronic antigenic stimulation. These alterations are defining features of the MCD genetic subtype within ABC-DLBCL. In contrast, GCB-DLBCL, comprising around 40% of cases, is enriched for mutations in epigenetic regulators such as EZH2 (21-22% frequency, leading to aberrant H3K27 trimethylation and gene silencing) and CREBBP (frequently inactivated, disrupting histone acetylation and p53 function).^[50]^[46]^[51] Epigenetic dysregulation is a hallmark of DLBCL, with mutations in histone modifiers like KMT2D (also known as MLL2) occurring in about 25% of cases across subtypes, primarily through inactivating frameshift or nonsense mutations that impair H3K4 methylation and disrupt B-cell differentiation genes. These changes, along with EZH2 and CREBBP alterations, alter chromatin accessibility and cooperate with other drivers to sustain proliferation. Recent advances in genomic profiling, including whole-genome sequencing as of 2025, have highlighted structural variants such as chromothripsis—catastrophic chromosome shattering events—in a substantial proportion of DLBCL cases, revealing complex rearrangements that accelerate tumor evolution.^[52]^[51]^[47] Clonal evolution in DLBCL is marked by intratumor heterogeneity, where diverse subclones harboring distinct mutations coexist within a single tumor, influenced by the microenvironment and therapy pressures. This heterogeneity drives resistance through Darwinian selection, with relapsed tumors often showing expansion of pre-existing subclones bearing mutations in genes like TP53 or epigenetic modifiers, leading to branched evolutionary patterns rather than linear progression. Spatial transcriptomic analyses underscore how stromal interfaces further amplify this heterogeneity, modulating gene expression programs such as MYC signaling in a site-specific manner.^[53]^[54]

Diagnosis and staging

Diagnostic methods

Diagnosis of diffuse large B-cell lymphoma (DLBCL) begins with a tissue biopsy, preferably an excisional or incisional biopsy of an affected lymph node, which reveals diffuse sheets of large lymphoid cells with prominent nucleoli and high nuclear-to-cytoplasmic ratios, often resembling centroblasts or immunoblasts.^[4] Fine-needle aspiration is inadequate as it fails to provide architectural context essential for accurate classification.^[55] Bone marrow biopsy may be performed in select patients to assess involvement, particularly if indicated by PET-CT or clinical suspicion, with involvement occurring in 10-30% of cases and patterns including paratrabecular aggregates or diffuse infiltration.^[56]^[57]^[58] Immunohistochemistry (IHC) is crucial for confirming B-cell lineage and subtyping, with a core panel including CD20 (positive in nearly all cases), CD3 (to exclude T-cell processes), and proliferation marker Ki-67, which typically shows a high index often exceeding 70-90% indicating aggressive behavior.^[55] For cell-of-origin (COO) subtyping, additional markers such as CD10, BCL6, and MUM1 are used via the Hans algorithm to distinguish germinal center B-cell-like (GCB) from activated B-cell-like (ABC) subtypes, with GCB showing CD10+ or (CD10- and BCL6+) and MUM1-, while ABC is MUM1+.^[59] Expression of BCL2 and MYC by IHC helps identify double-expressor lymphomas when both exceed 50% and 40%, respectively, prompting further molecular testing.^[55] Molecular testing complements IHC, with fluorescence in situ hybridization (FISH) routinely performed to detect translocations involving MYC (8q24), BCL2 (18q21), and BCL6 (3q27), defining high-grade or double-hit lymphomas when present.^[59] Polymerase chain reaction (PCR) for immunoglobulin heavy chain (IGH) gene rearrangements confirms clonality in ambiguous cases.^[4] As of 2025, liquid biopsy using circulating tumor DNA (ctDNA) has emerged for non-invasive genotyping, detecting mutations like MYD88 or CD79B and monitoring minimal residual disease (MRD) with high sensitivity in peripheral blood.^[60] Imaging plays a key role in initial assessment, with positron emission tomography-computed tomography (PET-CT) preferred for its ability to evaluate metabolic activity using fluorodeoxyglucose uptake, where the Deauville five-point scale is applied to interpret interim scans but also informs baseline disease extent.^[4] Contrast-enhanced CT of the neck, chest, abdomen, and pelvis is an alternative in resource-limited settings.^[55]

Staging and prognostic indices

Staging of diffuse large B-cell lymphoma (DLBCL) primarily follows the Ann Arbor system, modified by the Lugano classification, to assess the extent of disease involvement in lymph nodes and extranodal sites. Stage I indicates involvement of a single lymph node region or a single extralymphatic organ or site without nodal involvement; stage II involves two or more lymph node regions on the same side of the diaphragm or localized involvement of an extralymphatic organ with regional lymph node involvement on the same side; stage III denotes involvement of lymph node regions on both sides of the diaphragm, potentially including the spleen or limited contiguous extralymphatic extension; and stage IV reflects diffuse or disseminated involvement of one or more extralymphatic organs, such as the bone marrow, liver, or lungs, with or without associated lymph node involvement.^[61] Modifiers include the "E" designation for contiguous extranodal extension beyond the lymph node region and the "B" suffix for the presence of systemic symptoms such as unexplained fever, drenching night sweats, or weight loss greater than 10% in six months. The Lugano classification, established in 2014 and reaffirmed without major revisions as of 2025, recommends positron emission tomography-computed tomography (PET-CT) using 18F-fluorodeoxyglucose as the primary imaging modality for initial staging in FDG-avid lymphomas like DLBCL, replacing the need for bone marrow biopsy in most cases when PET-CT is positive.^[62] Response assessment under the Lugano criteria utilizes the Deauville 5-point scale, which scores residual FDG uptake on PET-CT relative to the liver and mediastinum to categorize complete metabolic response (scores 1-3), partial metabolic response (score 4 with reduced uptake), no metabolic response (score 4 with no reduction), or progressive metabolic disease (score 5). This scale facilitates standardized evaluation of treatment efficacy, with scores 1-3 indicating complete response and score 4 often requiring biopsy confirmation for equivocal cases. Prognostic indices stratify patients by baseline risk to guide therapeutic decisions and predict outcomes in DLBCL. The International Prognostic Index (IPI), developed in 1993, incorporates five independent risk factors: age greater than 60 years, elevated serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, Ann Arbor stage III or IV, and involvement of more than one extranodal site. Patients are grouped into four risk categories—low (0-1 factors), low-intermediate (2 factors), high-intermediate (3 factors), and high (4-5 factors)—with corresponding 5-year overall survival rates of approximately 73%, 51%, 43%, and 26%, respectively, in the pre-rituximab era. The revised IPI (R-IPI), introduced in 2007 for the rituximab era, reclassifies these factors into three groups—very good (0 factors), good (1-2 factors), and poor (3-5 factors)—yielding improved 4-year overall survival predictions of 94%, 79%, and 55%, respectively, reflecting the enhanced efficacy of rituximab combined with chemotherapy.^[63] This index better discriminates outcomes in patients receiving immunochemotherapy, though its prognostic value persists across molecular subtypes, with activated B-cell-like DLBCL generally associated with inferior survival compared to germinal center B-cell-like.^[63] For assessing central nervous system (CNS) relapse risk, the CNS-IPI, validated in 2016, builds on IPI factors with the addition of kidney or adrenal gland involvement, stratifying patients into low (0-1 points, <1% 2-year CNS relapse risk), intermediate (2-3 points, ~3-10% risk), and high (4-6 points, >10% risk) groups to identify candidates for prophylactic interventions.

Subtypes and variants

Diffuse large B-cell lymphoma, not otherwise specified (NOS)

Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) serves as the primary diagnostic category for the majority of DLBCL cases that do not meet criteria for morphologically, clinically, or molecularly defined subtypes under the 5th edition of the World Health Organization classification of haematolymphoid tumours. This entity encompasses a heterogeneous population of aggressive B-cell neoplasms lacking distinctive features that would relegate them to more specific variants, representing approximately 70-80% of all DLBCL diagnoses after exclusion of entities such as high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or primary mediastinal large B-cell lymphoma.^[8]^[9] The heterogeneity of DLBCL, NOS is underscored by its variable clinical behavior and molecular profiles, yet it remains a diagnosis of exclusion that highlights the evolving precision in lymphoma classification.^[11] Morphologically, DLBCL, NOS is defined by a diffuse proliferation of medium-to-large neoplastic B cells with nuclear diameters at least twice that of normal small lymphocytes, often featuring centroblasts (cells with multiple peripheral nucleoli) or immunoblasts (cells with central nucleoli and basophilic cytoplasm). The growth pattern is typically effacing, with a background of small lymphocytes, histiocytes, and occasional necrosis, though sclerosis or fibrosis may be present in some cases. Immunophenotypically, tumor cells consistently express pan-B-cell antigens including CD19, CD20, CD22, CD79a, and PAX5, while surface immunoglobulin is usually absent; the cell-of-origin (COO) subtype—germinal center B-cell-like (GCB) or activated B-cell-like (ABC)—is determined by variable expression of CD10, BCL6, and MUM1/IRF4, with approximately 50% of cases classified as GCB and 40% as ABC via immunohistochemistry algorithms like Hans or COO.^[11]^[5] Ki-67 proliferation indices are high (often >40%), reflecting the aggressive nature of the disease.^[4] Clinically, DLBCL, NOS predominantly manifests with lymphadenopathy, though up to 40% of cases involve extranodal sites such as the gastrointestinal tract, skin, or bone; it most commonly affects older adults with a median age of 70 years and a slight male predominance. With the integration of genomic profiling in diagnostic workflows, recent studies indicate that post-reclassification, NOS constitutes about 60% of DLBCL cases, as advanced molecular tools identify an increasing number of genetically defined subtypes.^[8] Standard frontline therapy involves R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) immunochemotherapy, applicable to the majority of NOS cases regardless of COO subtype.^[47] Recognized morphological variants within DLBCL, NOS include T-cell/histiocyte-rich large B-cell lymphoma (TCHRLBCL), accounting for 10-15% of cases, characterized by scattered large atypical B cells (<10% of the infiltrate) amid a predominant background (>90%) of small T cells and histiocytes without forming granulomas; this variant often presents in younger patients with advanced-stage disease but carries a better prognosis, with 5-year overall survival rates around 66-85% compared to 60% for conventional DLBCL, NOS. Another variant features plasmablastic morphology, where tumor cells exhibit eccentric nuclei, abundant amphophilic cytoplasm, and plasmacytic differentiation (e.g., CD138 expression with reduced CD20), comprising a smaller proportion of NOS cases and associated with more aggressive behavior, though distinct from the separate entity of plasmablastic lymphoma.^[64]^[65]^[66]

Specific subtypes

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a distinct subtype characterized by a rapidly growing mediastinal mass, often presenting with superior vena cava syndrome or respiratory distress, predominantly affecting young adults with a female predominance (M:F ratio 1:2). Morphologically, it features medium to large lymphoid cells resembling centroblasts or immunoblasts, with compartmentalizing sclerosis; immunophenotypically, tumor cells express B-cell markers such as CD20 and CD19, along with CD30, MAL, and PD-L1/PD-L2 in most cases, while lacking surface immunoglobulin. In the 5th edition of the WHO classification (2022), PMBCL remains a separate entity due to its unique genetic profile, including frequent 9p24.1 gains leading to JAK/STAT pathway activation and overlap with classic Hodgkin lymphoma in mediastinal gray zone cases.^[8]^[9] Intravascular large B-cell lymphoma (IVLBCL) is a rare, aggressive variant where neoplastic large B-cells are confined to the lumina of small blood vessels, leading to multi-organ dysfunction without discrete mass formation; it typically affects elderly adults without gender preference, manifesting as cutaneous lesions, neurological symptoms, or a hemophagocytic syndrome in Asian cohorts. Morphologically, the cells are large with prominent nucleoli and scant cytoplasm, filling vascular spaces; immunophenotypically, they express pan-B-cell antigens like CD20 and CD79a, often with CD5 co-expression and non-germinal center B-cell features, alongside frequent MYD88 and CD79B mutations. The 2022 WHO classification retains IVLBCL as a distinct subtype, emphasizing its three clinical variants (Western, Asian, and cutaneous) and poor prognosis if undiagnosed antemortem.^[9]^[67] Primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL) arises exclusively within the CNS parenchyma or vitreoretinal compartment, primarily in elderly immunocompetent patients (median age >60 years) with a slight male predominance, presenting with focal neurological deficits, cognitive changes, or B symptoms. It exhibits diffuse perivascular infiltration by large centroblastic or immunoblastic cells; immunophenotypically, tumors are positive for CD20, BCL2, BCL6, and MUM1/IRF4, rarely CD10, and frequently harbor MYD88 L265P mutations. Under the 2022 WHO framework, PCNS-DLBCL is grouped with other large B-cell lymphomas of immune-privileged sites (including testicular and vitreoretinal), highlighting shared molecular alterations like PIM1 and CDKN2A disruptions and its notoriously poor prognosis despite intensive therapy.^[8]^[9] Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), represents an aggressive skin-confined neoplasm typically arising on the lower legs of elderly patients (median age 75 years) with a marked female predominance (M:F 1:2-4), manifesting as solitary or multiple erythematous nodules or plaques that may ulcerate. Histologically, it shows dense dermal and subcutaneous infiltrates of large immunoblasts and centroblasts without folliculotropic growth; immunophenotypically, cells express CD20, BCL2 (strong), MUM1/IRF4, and FOXP1, with activated B-cell-like features and common MYD88 mutations, but negative for CD10 and BCL6. The 2022 WHO classification confirms PCDLBCL-LT as a separate entity from other cutaneous B-cell lymphomas, noting its 5-year disease-specific survival of approximately 50-60% and potential for extracutaneous spread in up to 20% of cases.^[9]^[68] Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is an aggressive subtype driven by EBV infection, affecting predominantly patients over 50 years without overt immunosuppression, though more common in Asia and Latin America (prevalence 10-15% vs. 5% in Western populations), with nodal or extranodal involvement including gastrointestinal tract and skin. Morphologically, it displays polymorphic infiltrates (70%) or monomorphic large cell sheets (30%) with frequent necrosis; immunophenotypically, neoplastic cells express pan-B-cell markers (CD20+, CD79a+, PAX5+), show activated B-cell-like gene expression in 75% of cases, and are positive for EBV-encoded RNA (EBER) in the majority (>80% per ICC 2022 criteria). The 2024 update emphasizes its distinct prognosis (5-year overall survival 57-82% with R-CHOP) and potential for PD-L1 expression as a therapeutic target, while the 2022 WHO classification integrates it into immune dysregulation-associated categories without the "NOS" suffix.^[69]^[9] Human herpesvirus 8 (HHV8)-associated large B-cell lymphoma arises in the context of multicentric Castleman disease or immunosuppression (e.g., HIV), primarily affecting adult males with severe immune deficiency, presenting with lymphadenopathy, splenomegaly, or effusions. It features diffuse proliferation of large plasmablastic B-cells; immunophenotypically, tumors express HHV8 latency-associated nuclear antigen, variable CD20 and CD138, and often lack typical B-cell markers, with activated B-cell-like features. In the 2022 WHO classification, HHV8+ DLBCL is recognized as a specific entity within KSHV/HHV8-associated lymphoproliferations, distinct from primary effusion lymphoma but overlapping in extracavitary forms, and associated with rapid progression if untreated.^[9]^[70] High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) was reclassified in the 2022 WHO edition as a separate category from DLBCL due to its aggressive biology and distinct genetic profile involving concurrent translocations, though significant morphologic and clinical overlap persists with DLBCL subtypes, particularly in cases lacking triple-hit features or arising from indolent precursors. Recent 2025 analyses highlight ongoing challenges in distinguishing these from DLBCL NOS, with shared adverse prognostic factors like central nervous system involvement.^[8]^[71]

Treatment

Initial therapy

The initial therapy for newly diagnosed diffuse large B-cell lymphoma (DLBCL) focuses on curative immunochemotherapy regimens tailored to disease stage and patient risk factors. The cornerstone treatment is R-CHOP, a combination of rituximab (a monoclonal anti-CD20 antibody), cyclophosphamide, doxorubicin, vincristine, and prednisone, administered in 21-day cycles. This regimen is given for 6 cycles in patients with advanced-stage disease (stages III/IV), achieving complete remission in approximately 60% of cases overall, with higher cure rates exceeding 80% in limited-stage presentations when combined with appropriate consolidative therapy.^[72]^[73] Treatment is stage-adapted to optimize efficacy and minimize toxicity. For limited-stage disease (stages I/II, non-bulky), abbreviated R-CHOP (3-4 cycles) followed by involved-site radiotherapy (ISRT) to residual sites is standard, particularly for patients with favorable International Prognostic Index (IPI) scores. In advanced stages, full-dose R-CHOP for 6 cycles remains the backbone, though dose-adjusted alternatives like DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) may be considered for select high-grade or double-hit lymphomas. Subtype-specific modifications include R-CHOP plus consolidative radiation for primary mediastinal B-cell lymphoma (PMBCL), a DLBCL variant often affecting young adults, to address bulky mediastinal disease. Additionally, for patients at high risk of central nervous system (CNS) relapse—such as those with testicular, breast, or paranasal sinus involvement—CNS prophylaxis with high-dose methotrexate (typically 3-4 g/m² intravenously) is integrated into the regimen, often after cycles 1-2 of R-CHOP, to reduce relapse risk without compromising systemic control.^[57]^[74] Supportive care is integral to managing treatment-related toxicities and ensuring regimen completion. Febrile neutropenia, a common complication of R-CHOP due to profound myelosuppression, occurs in up to 20-30% of patients without prophylaxis; primary use of granulocyte colony-stimulating factor (G-CSF, such as pegfilgrastim) is recommended for all patients to prevent delays or dose reductions. For high-risk patients (e.g., those with elevated IPI scores or double-/triple-hit molecular features), the 2023 FDA approval (with ongoing 2025 endorsements in guidelines) of polatuzumab vedotin—a CD79b-directed antibody-drug conjugate—combined with R-CHP (omitting vincristine to reduce neuropathy) offers an alternative frontline option, demonstrating improved progression-free survival over standard R-CHOP in phase 3 trials while maintaining comparable tolerability.^[75]^[76]

Management of relapsed or refractory disease

For patients with diffuse large B-cell lymphoma (DLBCL) who experience relapse after initial therapy such as R-CHOP or do not respond to frontline treatment, management focuses on salvage regimens to achieve chemosensitivity, followed by consolidation with autologous stem cell transplantation (ASCT) in eligible candidates. Standard second-line approaches include platinum-based chemotherapy regimens like rituximab-ifosfamide-carboplatin-etoposide (R-ICE) or rituximab-dihydrogenase-ara-C-platinum (R-DHAP), which induce complete remission (CR) in approximately 40-60% of chemosensitive cases, enabling subsequent ASCT that can yield long-term remission in about 50% of such patients.^[77]^[78] Prognostic factors, such as double-hit lymphoma status, often predict poorer responses to these salvage therapies and influence the selection of alternative strategies.^[79] In transplant-eligible patients with early relapse (within 12 months) or refractory disease, chimeric antigen receptor T-cell (CAR-T) therapies targeting CD19 represent a cornerstone of treatment, particularly after failure of salvage chemotherapy. For high-risk patients relapsing early (within 12 months) or with double-hit lymphoma, CAR-T therapy is now FDA-approved as second-line treatment, often preferred over salvage chemotherapy followed by ASCT in eligible patients. Axicabtagene ciloleucel (axi-cel), FDA-approved for second-line therapy in high-risk R/R large B-cell lymphoma and after two prior lines, and tisagenlecleucel (tisa-cel), FDA-approved after at least two prior lines, achieve CR rates of 40-50% in heavily pretreated refractory populations, with durable remissions observed in up to 30-40% at 2 years in real-world settings.^[80]^[81]^[82] Bridging therapies, such as gemcitabine-oxaliplatin (GemOx) or ICE, are often used prior to CAR-T infusion to control disease progression.^[57] For patients ineligible for ASCT or CAR-T, targeted immunotherapies have expanded options, including bispecific T-cell engagers like glofitamab and epcoritamab, which received FDA approval in 2023 for R/R DLBCL after two or more prior therapies. These agents, administered subcutaneously, elicit CR rates of 25-40% as monotherapy in third-line settings, offering outpatient feasibility and reduced cytokine release syndrome incidence compared to CAR-T.^[83]^[84] In non-transplant candidates, the combination of tafasitamab (an anti-CD19 antibody) with lenalidomide provides an alternative, achieving CR in about 40% of transplant-ineligible R/R patients based on phase II data, with manageable toxicity.^[85] For localized relapse, involved-site radiotherapy (ISRT) serves as a palliative or consolidative option, controlling disease in 50-70% of cases.^[57] The 2025 therapeutic landscape for R/R DLBCL emphasizes precision approaches, such as tazemetostat, an EZH2 inhibitor approved for EZH2-mutated follicular lymphoma but showing objective responses in 20-30% of relapsed EZH2-mutated DLBCL cases in phase II trials.^[86] Ongoing trials for antibody-drug conjugates (ADCs), including loncastuximab tesirine (approved post-2021 for third-line use with CR rates around 25%) and emerging agents like polatuzumab vedotin in combination with GemOx, report overall response rates of 50-60% in R/R settings, addressing unmet needs in multiply relapsed disease.^[87]^[88] Clinical trials remain integral, prioritizing enrollment to access novel combinations.^[57]

Prognosis

Survival outcomes

Diffuse large B-cell lymphoma (DLBCL) exhibits favorable survival outcomes in the modern era of immunochemotherapy, with the standard R-CHOP regimen achieving a 5-year overall survival (OS) rate of 60-70% across all patients.^[89] Recent data from the POLARIX trial as of 2024 indicate 5-year OS estimates of approximately 80% with R-CHOP in trial cohorts.^[90] For limited-stage disease (stages I-II), 5-year OS rates approach 80-90%, reflecting high curability with abbreviated therapy and radiation when appropriate.^[73] In contrast, advanced-stage disease (stages III-IV) yields lower 5-year OS rates of approximately 50-60%. Prior to the introduction of rituximab in the early 2000s, 5-year OS rates for DLBCL hovered around 40-50%, primarily due to reliance on chemotherapy alone such as CHOP.^[91] The addition of rituximab to chemotherapy marked a significant advancement, improving 5-year OS by approximately 10-20% and establishing long-term cure rates exceeding 60% in many cohorts, with further gains attributed to refined staging, supportive care, and targeted consolidations.^[92] Survival varies markedly by molecular subtype, with germinal center B-cell-like (GCB) DLBCL demonstrating superior outcomes compared to activated B-cell-like (ABC) DLBCL; 3-year progression-free survival (PFS) rates are approximately 75% for GCB versus 40-50% for ABC following R-CHOP.^[93] High-grade subtypes such as double-hit lymphoma, characterized by rearrangements in MYC and BCL2/BCL6, portend particularly poor prognosis, with 5-year OS rates often 20-30% under standard therapy.^[94] For relapsed or refractory DLBCL, outcomes have improved with chimeric antigen receptor T-cell (CAR-T) therapy; as of 2025, 2-year OS rates post-CAR-T infusion reach 30-45% in real-world settings, representing a substantial advance over historical salvage approaches.^[95] These gains highlight the potential for durable remissions in otherwise chemorefractory disease, though long-term follow-up remains essential.

Prognostic factors

Several clinicopathologic variables serve as established prognostic factors in diffuse large B-cell lymphoma (DLBCL), influencing overall survival (OS) independent of composite indices. Adverse factors include age greater than 60 years, poor performance status (Eastern Cooperative Oncology Group score >1), elevated lactate dehydrogenase (LDH) levels, and involvement of more than one extranodal site, which collectively identify high-risk patients with approximately 53% 5-year OS per the revised International Prognostic Index (R-IPI) in the R-CHOP era.^[96] In contrast, limited-stage disease (stages I-II) is favorable, associated with 70-80% 10-year OS.^[96] Molecular subtyping further refines prognosis, with the germinal center B-cell (GCB) subtype linked to superior outcomes compared to the activated B-cell (ABC) subtype when treated with standard immunochemotherapy. Patients with GCB-DLBCL exhibit a 3-year progression-free survival (PFS) of approximately 75%, whereas ABC-DLBCL is associated with poorer responses and 3-year PFS of 40-50%.^[96]^[97] High-grade genetic features, such as double-hit (MYC and BCL2 or BCL6 rearrangements) or triple-hit lymphomas, confer an aggressive course and inferior prognosis, with median OS historically as low as 18-24 months under standard regimens, though intensified therapies can mitigate this risk.^[98] Interim positron emission tomography (PET) assessment using the Deauville 5-point scale provides dynamic prognostic insight, where scores of 1-3 (low uptake) after 2-4 cycles of therapy indicate favorable response and 2-year PFS exceeding 85%, outperforming baseline metrics.^[96]^[99] Emerging biomarkers, including circulating tumor DNA (ctDNA) levels post-therapy, offer enhanced risk stratification; undetectable ctDNA at treatment end predicts 97% 2-year PFS, while persistence signals high relapse risk (29% 2-year PFS, hazard ratio 28.7).^[100] Within the tumor microenvironment, high programmed death-ligand 1 (PD-L1) expression on neoplastic cells correlates with aggressive features and reduced OS, though microenvironmental PD-L1 may confer a protective effect in some contexts.^[101]^[102] Comorbidities, particularly cardiovascular disease such as preexisting heart failure, adversely affect DLBCL prognosis by limiting chemotherapy tolerance (e.g., reduced anthracycline use, odds ratio 0.55) and increasing lymphoma-specific mortality (hazard ratio 1.24), with 1-year mortality rates of 41.8% versus 29.6% in those without heart failure.^[103]

Helicobacter pylori-associated diffuse large B-cell lymphoma

Helicobacter pylori-associated diffuse large B-cell lymphoma (DLBCL) arises in the setting of chronic gastric infection, where persistent antigenic stimulation drives B-cell proliferation. Chronic H. pylori gastritis induces the formation of mucosa-associated lymphoid tissue (MALT), which can progress to low-grade MALT lymphoma; a small proportion (less than 10%) of these cases transform into high-grade DLBCL through ongoing antigen-driven B-cell receptor (BCR) signaling, leading to genetic instability and clonal expansion.^[104]^[105]^[106] This pathogenesis highlights the bacterium's role in fostering an inflammatory microenvironment that promotes lymphomagenesis, distinct from de novo DLBCL. Patients typically present with gastric symptoms such as epigastric pain, dyspepsia, or nausea, often accompanied by endoscopic findings of gastric masses or ulcers. In gastric DLBCL cases, H. pylori infection is identified in 50-60% of instances, underscoring its etiological relevance in this subset.^[107]^[108] Diagnosis involves upper endoscopy with biopsy to identify DLBCL histological features, including large B-cell morphology and immunohistochemical markers like CD20 positivity, often coexisting with residual MALT components. H. pylori status is confirmed through non-invasive methods such as the urea breath test or invasive approaches like histological staining (e.g., Giemsa) on biopsy samples.^[107]^[109] Treatment begins with H. pylori eradication therapy using a combination of antibiotics (e.g., clarithromycin, amoxicillin, metronidazole) and a proton pump inhibitor, which induces complete remission in 50-75% of early-stage cases by eliminating the antigenic drive. For advanced or non-responsive disease, standard DLBCL regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) are employed, often yielding favorable outcomes in this less aggressive H. pylori-linked variant.^[110]^[111]^[112]

Epstein-Barr virus-positive lymphoproliferative disorders

Epstein-Barr virus-positive (EBV+) lymphoproliferative disorders represent a heterogeneous group of B-cell malignancies driven by latent EBV infection, which promotes lymphoproliferation through mechanisms such as immune evasion and oncogenic signaling. In the context of diffuse large B-cell lymphoma (DLBCL), EBV+ DLBCL, not otherwise specified (NOS), is a distinct aggressive subtype characterized by EBV infection in the majority of lymphoma cells, typically without underlying severe immunosuppression. This entity is classified separately from other EBV-associated conditions like post-transplant lymphoproliferative disorders (PTLD), as it predominantly occurs in immunocompetent hosts, particularly the elderly.^[113] Epidemiologically, EBV+ DLBCL accounts for approximately 5% of DLBCL cases in Western populations but shows higher prevalence (8-11%) in East Asia, affecting patients with a median age of around 70 years. Risk factors include advanced age-related immunosenescence, which impairs EBV-specific T-cell immunity, allowing viral persistence and transformation of B-cells. Unlike EBV-negative DLBCL, this subtype often presents with extranodal involvement in sites such as the skin, gastrointestinal tract, or central nervous system, alongside lymphadenopathy, and is associated with high International Prognostic Index (IPI) scores reflecting aggressive disease.^[113]^[114]^[115] Pathologically, EBV+ DLBCL features large neoplastic B-cells expressing CD20 and EBV-encoded small RNA (EBER) in over 50% of tumor cells, confirming viral association. Molecularly, it exhibits distinct genetic alterations compared to EBV-negative DLBCL, including frequent mutations in immune evasion genes like SOCS1 (24%), CD58 (11%), and B2M (11%), as well as epigenetic regulators such as KMT2D (22%) and KMT2C (17%). These changes, alongside EBV-driven activation of pathways like NF-κB via latent membrane protein 1 (LMP1) and JAK-STAT signaling, contribute to oncogenesis and resistance to apoptosis. Amplification of 9p24.1 (20% of cases) leads to PD-L1/PD-L2 overexpression, enhancing tumor immune escape. Cell-of-origin subtyping reveals an activated B-cell-like (ABC) predominance in about 43% of cases, with 27% germinal center B-cell-like (GCB) and 30% unclassified.^[115]^[113]^[114] Treatment for EBV+ DLBCL mirrors that of conventional DLBCL, with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as the frontline regimen, though outcomes are inferior, particularly in elderly patients. The 5-year overall survival rate is approximately 30-40%, worse than the 50-60% seen in EBV-negative counterparts, due to factors like frailty and treatment intolerance. Emerging approaches target EBV-specific mechanisms, such as PD-1/PD-L1 inhibitors for amplified cases or CD30-directed therapies, showing promise in relapsed settings. In younger patients without comorbidities, survival approximates that of EBV-negative DLBCL. Prognosis improves with early detection and rituximab incorporation, but immunosenescence remains a key adverse factor.^[113]^[114]^[115]

References

[1]
Aggressive B-Cell Non-Hodgkin Lymphoma Treatment (PDQ®) - NCI
May 12, 2025 · Diffuse Large B-Cell Lymphoma. Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL and makes up 30% of newly diagnosed cases.
[2]
Non-Hodgkin Lymphoma Treatment - NCI - National Cancer Institute
Aug 22, 2024 · Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. It grows quickly in the lymph nodes and often the spleen, liver, ...
[3]
Diffuse large B-cell lymphoma - Symptoms and causes - Mayo Clinic
Jun 18, 2025 · These may include nausea, vomiting, fatigue, fever, rash, diarrhea and others. Harmful side effects from treatments may include:
[4]
Diffuse Large B-Cell Lymphoma - StatPearls - NCBI Bookshelf - NIH
Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma, accounting for about 25% to 30% of all the non-Hodgkin lymphomas.Etiology · Pathophysiology · Treatment / Management<|control11|><|separator|>
[5]
9680/3 Diffuse large B-cell lymphoma, NOS (DLBCL) - SEER
Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of medium or large B lymphoid cells whose nuclei are the same size as, or larger than, those of normal ...
[6]
Lymphoma classification and the tools of our trade: an introduction ...
Jan 2, 2013 · This review begins with the Rappaport classification, initially published in 1956 in a publication on follicular lymphomas (Table 1). It was ...
[7]
Advances in the biology and therapy of diffuse large B-cell lymphoma
In the REAL classification, the diagnosis of DLBCL was expanded to include B-cell tumors previously designated as immunoblastic lymphomas.Pathologic classifications · Genetic and biologic... · Evolution of empiric therapy
[8]
The 5th edition of the World Health Organization Classification of ...
Jun 22, 2022 · Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) represents the most common entity, and is defined by large-cell morphology ...
[9]
Large B-Cell Lymphomas in the 5th Edition of the WHO ...
Diffuse large B-cell lymphomas constitute the most common type of Non-Hodgkin lymphoma in the Western world, comprising 30–40% of cases with slight over- ...
[10]
A New Immunostain Algorithm Classifies Diffuse Large B-Cell ...
Abstract. Purpose: Hans and coworkers previously developed an immunohistochemical algorithm with ∼80% concordance with the gene expression profiling (GEP)
[11]
DLBCL, NOS - Pathology Outlines
Sep 18, 2024 · DLBCL, NOS · B cell markers (CD20, PAX5, CD79a, CD19, CD22) · Cell of origin subtyping: CD10 (30 - 50%), MUM1 (35 - 65%), BCL6 (60 - 90%) ...
[12]
https://emedicine.medscape.com/article/202969-workup
[13]
A rare presentation of ovarian diffuse large B-cell lymphoma: A case ...
Diffuse large B-cell lymphoma (DLBCL) is one of the most common causes of non ... About 70% of affected individuals will present with lymphadenopathy [2].
[14]
Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics) - UpToDate
### Signs and Symptoms of DLBCL
[15]
https://www.cancervic.org.au/about-cancer/types/statistics/diffuse-large-b-cell-lymphoma-statistics.html
[16]
Clinicopathologic features and outcomes of diffuse large B-cell ...
Extranodal involvement is seen in about 40%–50% of the cases of diffuse large B-cell lymphoma (DLBCL). However, data on the clinicopathological features and ...
[17]
How I manage autoimmune cytopenias in patients with lymphoid ...
Mar 10, 2022 · AIHA is best characterized in chronic lymphocytic leukemia (CLL), but is found as a complication in many lymphoma entities and in solid tumors.
[18]
Small-bowel B-cell lymphoma presenting as autoimmune hemolytic ...
This case highlights the occurrence of two conditions leading to severe anemia. Whenever an AIHA is present, the clinician must be aware of lymphomas.
[19]
Epidemiology and etiology of diffuse large B-cell lymphoma - PubMed
Nov 27, 2023 · Globally, DLBCL accounts for a third of all NHLs, ranging between 20% and 50% by country. Based on United States (U.S.) cancer registry data, ...
[20]
Sex differences in lymphoma incidence and mortality by subtype
We identified 36 795 lymphoma cases, 20 738 (56.4%) in men and 16 057 (43.6%) in women. Men were at significantly higher risk of 14 out of 16 lymphoma subtypes ...
[21]
Epidemiology and etiology of diffuse large B-cell lymphoma
Globally, DLBCL accounts for a third of all NHLs, ranging between 20% and 50% by country. Based on United States (U.S.) cancer registry data, age-standardized ...
[22]
Familial predisposition and genetic risk factors for lymphoma - PMC
One striking finding is the clustering of risk by NHL subtype. For example, first-degree relatives of DLBCL cases had a 9.8-fold increased risk of DLBCL,24 ...
[23]
Diffuse Large B-Cell Lymphoma in the HIV Setting - PubMed Central
Jun 15, 2023 · DLBCL is the most common NHL subtype affecting PWH. There are two morphological variants of HIV-related DLBCL, centroblastic variant and ...
[24]
djaf244.pdf - Oxford Academic
Aug 26, 2025 · 17,18. Although the relative risk of DLBCL among people with HIV com- pared with the general population declined from 23 times higher between ...<|separator|>
[25]
Risk of diffuse large B-cell lymphoma after solid organ ... - NIH
Immunosuppression has been associated with strikingly high risks of diffuse large B-cell lymphoma (DLBCL), a common and clinically aggressive lymphoma (29). A ...Missing: autoimmune | Show results with:autoimmune
[26]
Autoimmune diseases and diffuse large B-cell lymphoma - Medicine
Jun 20, 2025 · Our MR results showed that ADs, such as Sjögren syndrome and systemic lupus erythematosus, may have causal relationship with DLBCL, while type 1 diabetes ...
[27]
Autoimmune/Inflammatory Arthritis Associated Lymphomas - NIH
For example, recent literature has indicated a positive correlation between severity of inflammation and risk of lymphomas among RA and Sjögren's syndrome ...
[28]
Insecticide exposure and farm history in relation to risk of ... - PubMed
Women aged less than 65 years who ever applied insecticides had 87% higher risk of DLBCL (95% CI = 1.13-3.09). Conclusions: Insecticide exposures may contribute ...
[29]
Current Understanding of Lifestyle and Environmental Factors and ...
Some evidence has emerged suggesting that obesity or higher BMI may increase the risk of NHL, particularly for specific histological subtypes including DLBCL.
[30]
Obesity, Diet and Risk of Non-Hodgkin Lymphoma - PMC - NIH
Two other large case-control studies found increased risks of DLCL associated with morbid obesity (BMI >35).
[31]
The microbiome-lymphoma Axis: A systematic review and Meta ...
Oct 30, 2025 · Our study concluded that DLBCL is associated with gut dysbiosis which is mainly characterized by a depletion of specific taxa of microbiota.
[32]
The causal relationship between gut microbiota and lymphoma
May 6, 2024 · Our study elucidates a definitive causal link between gut microbiota and lymphoma development, pinpointing specific microbial taxa with potential causative ...
[33]
Large B-cell lymphoma imprints a dysfunctional immune phenotype ...
Sep 11, 2025 · Accordingly, inflammatory cytokines are commonly elevated in the serum of patients with DLBCL.24,25. Despite frequently reported inflammation at ...
[34]
Diffuse large B-cell lymphoma microenvironment displays a ...
May 2, 2023 · We found a clear prominence of macrophages in the DLBCL microenvironment. Particularly, the proportions of resting M0 and pro-inflammatory M1 ...
[35]
Circulating IL6 is involved in the infiltration of M2 macrophages and ...
Mar 13, 2025 · Serum IL6 testing has also revealed an association between its levels and diffuse large B cell lymphoma (DLBCL) occurrence. There is limited ...
[36]
Insights into the tumor microenvironment of B cell lymphoma
Dec 29, 2022 · Here, we review the normal function of different components of the TME, the impact of their aberrant behavior in B cell lymphoma and the current TME-direct ...T Follicular Helper Cells · T Regulatory Cells · Myeloid-Derived Suppressor...<|separator|>
[37]
An updated understanding of follicular lymphoma transformation
Oct 9, 2025 · In the prerituximab era, reports from large heterogeneous cohorts estimated the annualized risk of transformation to DLBCL at ∼2% to 3% per year ...
[38]
Lymphoma dissemination: the other face of lymphocyte homing | Blood
These tumors usually display tissue-specific dissemination patterns and express homing receptors corresponding to the tissue of origin. Figure 3. Figure 3 ...
[39]
Critical role of PI3K signaling for NF-κB–dependent survival in ... - NIH
We have shown that constitutive activation of the PI3K pathway is a common feature of ABC DLBCL cells. PI3K or PDK1 inhibition affects viability, MALT1 ...
[40]
Targeting B-cell receptor and PI3K signaling in diffuse large B-cell ...
Sep 30, 2021 · ... NF-κB and PI3K pathway activation.15 A hallmark of ABC DLBCLs is chronic active BCR signaling and BCR clustering on the cell surface (Figure 1).
[41]
Leucyl-tRNA synthetase promotes malignant progression in diffuse ...
Aug 7, 2025 · These findings demonstrate that LARS deficiency impairs glycolytic metabolism and attenuates the malignant behavior of DLBCL cells, providing ...
[42]
SH3BP5-driven metabolic-immune crosstalk in DLBCL: a prognostic ...
Sep 24, 2025 · Mechanistically, pathway enrichment and metabolic assays indicated that SH3BP5 is linked to mitochondrial metabolic reprogramming, promoting ...
[43]
Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma
Apr 11, 2018 · Although most NOTCH1 mutant cases were ABC DLBCL, none had CD79B or MYD88L265P mutations and their predictor scores were significantly lower ...
[44]
Diffuse large B cell lymphoma (DLBCL)
Feb 15, 2025 · Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin's lymphoma that arises from the germinal center.
[45]
Mutational profile and prognostic significance of TP53 in ... - NIH
The 5-year OS was 65.9% for patients with WT-TP53 versus 47.8% for those with MUT-TP53 DLBCL. The median PFS for patients with WT-TP53 DLBCL was 93.14 months ...
[46]
High grade B-cell lymphoma with rearrangements of MYC and BCL2 ...
Earlier studies using fluorescent in situ hybridization (FISH) reported that 7% to 10% of DLBCL harbored MYC, BLC2 and/or BCL6 translocations, and were called “ ...
[47]
High prevalence of oncogenic MYD88 and CD79B mutations in ...
Sep 6, 2013 · Activating mutations in CD79 and MYD88 have recently been found in a subset of diffuse large B-cell lymphoma (DLBCL), identifying B-cell receptor and MYD88 ...
[48]
Molecular Pathogenesis of Diffuse Large B-Cell Lymphoma - PMC
EZH2 mutations were observed in 21.7% of GCB DLBCL cases. WGS indicated that inactivating mutations in GNA13 (Gα protein) were prevalent in GCB DLBCL cases.
[49]
Genetic and epigenetic determinants of diffuse large B-cell lymphoma
Dec 4, 2020 · As was just stated, KMT2D (sometimes called MLL2 or MLL4) is the most commonly mutated gene in DLBCL, with ~25% of cases showing genetic ...
[50]
https://www.nature.com/articles/bcj201328
[51]
Deep sequencing reveals clonal evolution patterns and mutation ...
Aug 15, 2014 · More generally, it is presently unclear whether clonal heterogeneity in primary tumors plays a role in DLBCL relapse. Previously, Ding et al ...
[52]
Diagnosis and Management of Diffuse Large B-Cell Lymphoma
Excisional/incisional biopsy is preferred. Morphologic diagnosis of DLBCL needs to be confirmed by using limited IHC, CD3, and CD20 (IIIB); 91% agreement (one ...
[53]
Biological Features and Prognostic Impact of Bone Marrow ...
Bone marrow (BM) is involved in 11–25% of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) [1,2,3,4]. It is well known that this involvement is not ...
[54]
Molecular Diagnostic Review of Diffuse Large B-Cell Lymphoma ...
Apr 27, 2022 · Diagnostic approaches to diffuse large B-cell lymphoma with comparative advantages and disadvantages to each method. Diagnostic Technology ...
[55]
Liquid Biopsy in B and T Cell Lymphomas: From Bench to Bedside
May 19, 2025 · In diffuse large-B-cell lymphoma (DLBCL), ctDNA facilitates non-invasive genotyping by identifying hallmark mutations (e.g., MYD88, CD79B ...
[56]
Lugano staging classification | Radiology Reference Article
Oct 16, 2025 · The Lugano staging classification is the lymphoma staging system that is most commonly used in clinical practice.
[57]
Current Status of Revisions to the Lugano Classification in Lymphoma
Jun 17, 2025 · The current classification should remain the standard until the clinical benefit of MTV and ctDNA are firmly established and practical considerations ...
[58]
The revised International Prognostic Index (R-IPI) is a ... - PubMed
The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma ...
[59]
Clinical features and survival of patients with T-cell/histiocyte-rich ...
Five-year overall survival in THRLBCL was 66% (95%CI, 60–71%). Adjusting for clinical and socio-economic covariates, THRLBCL was associated with better survival ...
[60]
T cell / histiocyte rich LBCL - Pathology Outlines
Overall 5 year survival rate is 66% (Leuk Lymphoma 2019;60:3426) · International Prognostic Index (IPI) score is used for risk stratification · References: Blood ...Missing: prevalence | Show results with:prevalence
[61]
Diffuse large B-cell lymphomas with plasmablastic differentiation ...
DLBCLs with plasmablastic differentiation are a heterogeneous group of neoplasms with different clinicopathological characteristics that may correspond to ...
[62]
Intravascular large B-cell lymphoma: a chameleon with multiple ...
This review focuses on histopathological characteristics, pathogenetic features, presenting symptoms, clinical variants, disease progression, prognostic ...Abstract · Introduction · Immunophenotype · Pathogenesis
[63]
Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
PCDLBCL, LT constitutes 2% of primary cutaneous lymphomas and mostly affects elderly women. It has a 5-year survival rate of 56%, and 10% of patients experience ...
[64]
EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified
Jul 3, 2024 · Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an aggressive B-cell lymphoma associated with EBV ...Abstract · DISEASE OVERVIEW · DIAGNOSIS · MANAGEMENT OF EBV+...
[65]
HHV8 positive DLBCL, NOS - Pathology Outlines
Jan 2, 2025 · HHV8 related diffuse large B cell lymphoma (DLBCL) is a neoplasm characterized by a monoclonal proliferation of HHV8 infected lymphoid cells ...
[66]
CNS relapse in high-grade B-cell lymphoma with MYC and BCL2 ...
Feb 6, 2025 · High-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2), or "double-hit lymphoma," has been associated with a high risk ...
[67]
R-CHOP Cancer Treatment - Cleveland Clinic
May 10, 2024 · The success rate of R-CHOP is excellent. Up to 70% of people diagnosed with diffuse large B-cell lymphoma (DLBCL) go into complete remission ...
[68]
Limited-stage diffuse large B-cell lymphoma | Blood
Feb 10, 2022 · Treatment. Contemporary strategies based on R-CHOP can cure >80% of patients with LS-DLBCL.10,21,26,31 However, multiple management ...
[69]
[PDF] NCCN Guidelines for Patients: Diffuse Large B-Cell Lymphomas
Feb 10, 2025 · CAR T-cell therapy is only used in recurrent lymphoma outside of clinical trials. CD19-directed CAR T-cell therapy options for DLBCL include ...
[70]
https://www.pathologyoutlines.com/topic/lymphomaHHV8DLBCL.html
[71]
Effects of primary granulocyte colony-stimulating factor (G-CSF ...
Sep 2, 2025 · The present study aims to investigate the impact of primary G-CSF prophylaxis on febrile neutropenia (FN) and other outcomes in DLBCL patients ...
[72]
Rituximab and ICE as second-line therapy before autologous stem ...
May 15, 2004 · RICE appears to induce very high CR rates in patients with relapsed and refractory DLBCL; however, further studies are necessary to determine ...
[73]
Autologous stem cell transplantation for relapsed/refractory large B ...
Jun 27, 2025 · Our results indicate that ASCT is a curative option for patients with chemosensitive disease especially in CR after salvage.Key Points · Patients and methods · Results · Discussion
[74]
Second-line treatment of diffuse large B‐cell lymphoma
The study results showed significant benefits in terms of event-free survival (EFS) (46% vs 12%) and OS rate (53% vs 32%) in the ASCT cohort, establishing ASCT ...
[75]
Clinical outcomes of tisagenlecleucel in relapsed/refractory diffuse ...
Aug 22, 2025 · Although CD19 CAR-T cell therapy brings prolonged survival outcomes and an improved cure rate for RR-DLBCL, it has been reported that more ...
[76]
Comparative real-world outcomes of CD19-directed CAR T-cell ...
In this retrospective multicenter cohort study, we evaluated real-world clinical outcomes of patients with relapsed/refractory LBCL treated with axicabtagene ...
[77]
New bispecific antibodies in diffuse large B-cell lymphoma - PMC
Epcoritamab and glofitamab are currently approved as monotherapy for relapsed and refractory DLBCL after at least two prior lines of therapy in Europe, the USA ...
[78]
Bispecific Monoclonal Antibodies in Diffuse Large B-Cell Lymphoma
Epcoritamab and glofitamab have received FDA and EMA approval for R/R DLBCL after two or more systemic line of therapies.
[79]
final 5-year efficacy and safety findings in the phase II L-MIND study
Feb 1, 2024 · Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/ ...
[80]
Tazemetostat for relapsed/refractory B-cell non-Hodgkin lymphoma ...
Aug 23, 2024 · Tazemetostat for relapsed/refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan: 3-year follow-up for a phase II study · Abstract.
[81]
ADC Therapeutics Announces Updated Data from LOTIS-7 Clinical ...
Jun 12, 2025 · The presentation highlights updated data as of April 14, 2025, in which r/r LBCL patients received dose levels of 120 µg/kg or 150 µg/kg of ...
[82]
Merck's Investigational Zilovertamab Vedotin at 1.75 mg/kg Dose ...
Zilovertamab vedotin 1.75 mg/kg in combination with R-GemOx achieved a 56.3% objective response rate (ORR) in patients with relapsed or refractory DLBCL.
[83]
A model to predict the prognosis of diffuse large B-cell lymphoma ...
Feb 27, 2023 · The 5-year survival rate for diffuse large B-cell lymphoma is about 60–70%. 60% of DLBCL patients could be cured with 6–8 courses of R-CHOP ...
[84]
Diffuse Large B-Cell Lymphoma (DLBCL) - Medscape Reference
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, representing approximately 30% of non-Hodgkin lymphomas (NHLs), and it is rapidly fatal ...Background · Pathophysiology · Etiology · Epidemiology
[85]
Cancer Stat Facts: NHL — Diffuse Large B-Cell Lymphoma (DLBCL)
The death rate was 1.7 per 100,000 men and women per year. These rates are age-adjusted and based on 2018–2022 cases and deaths. Additional Information.
[86]
Recent survival trends in diffuse large B‐cell lymphoma
Our study shows an improvement in the outcomes of DLBCL patients beyond the introduction of rituximab, although the magnitude of improvement is small.
[87]
Current Frontline Treatment of Diffuse Large B-Cell Lymphoma
Jan 20, 2022 · Outcomes differ for patients with GCB vs ABC DLBCL, with 5-year progression-free survival (PFS) of 75% vs 40%, respectively, after R-CHOP.
[88]
The high-grade B-cell lymphomas: double hit and more | Blood
Dec 19, 2024 · TP53 mutations are frequent events in double-hit B-cell lymphomas with MYC and BCL2 but not MYC and BCL6 translocations . Leuk Lymphoma.
[89]
Long-term outcomes of CAR-T cell therapy in DLBCL.
May 28, 2025 · Results: Survival outcomes: Median OS was 15.6 months (95% CI: 13.1–18.7), with 2- and 1-year survival rates of 45% and 65% respectively. Median ...
[90]
Diffuse large B-cell lymphoma in the new era: prognostic tools for ...
Oct 20, 2025 · The NCCN-IPI (National Comprehensive Cancer Network International Prognostic Index) is a revised prognostic tool for DLBCL that improves risk ...
[91]
ABC, GCB, and Double-Hit Diffuse Large B-Cell Lymphoma - PubMed
ABC DLBCL is associated with substantially worse outcomes when treated with standard chemoimmunotherapy. In addition to GCB and ABC subtypes, double-hit ...
[92]
Prognostic Value of 18F-FDG PET/CT in Diffuse Large B-Cell ...
Apr 1, 2023 · Our study confirmed the prognostic value of baseline MTV and interim ΔSUVmax in DLBCL. Combining interim Deauville score with interim ΔSUVmax ...
[93]
Remission Assessment by Circulating Tumor DNA in Large B-Cell ...
Aug 13, 2025 · Ultrasensitive ctDNA detection after frontline LBCL therapy is more prognostic than conventional radiographic response criteria. A refined ...
[94]
Programmed death ligand 1 expression in diffuse large B cell ...
May 8, 2023 · This study suggests that high PD-L1 expression in DLBCL is associated with aggressive clinicopathological features and a decreased response to R-CHOP.
[95]
Comprehensive Analysis of Tumor Microenvironment and PD-L1 ...
Sep 6, 2025 · The tumor microenvironment (TME) influences diffuse large B-cell lymphoma (DLBCL) progression, but the prognostic roles of tumor-infiltrating T- ...Table 1 · Table 2 · Table 4
[96]
Association of Preexisting Heart Failure With Outcomes in Older ...
Mar 29, 2023 · In this study, preexisting HF in patients with newly diagnosed DLBCL was common and was associated with lower use of anthracyclines and lower use of any ...
[97]
Helicobacter pylori and mucosa-associated lymphoid tissue
Dec 6, 2013 · Low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach, gastric MALT lymphoma, is associated with Helicobacter pylori infection.
[98]
Primary Gastric Lymphoma, Epidemiology, Clinical Diagnosis, and ...
May 21, 2018 · Many authors have described potential risk factors associated with the pathogenesis of PGL, including infection by Helicobacter pylori (H pylori) ...
[99]
Prognostic significance of helicobacter pylori-infection in gastric ...
Aug 28, 2019 · H. pylori status in de novo gastric DLBCL can be a promising predictor of disease outcome, and patients with negative H. pylori status require careful follow- ...
[100]
Gastric Non-Hodgkin Lymphoma in a Helicobacter pylori-Infected
The clinical presentation of PG-DLBCL is usually nonspecific, ranging from vague symptoms, including dyspepsia, epigastric pain or discomfort, to more serious ...
[101]
Helicobacter pylori eradication therapy is effective in the treatment of ...
May 24, 2012 · An explorative study evaluates the efficacy of Helicobacter pylori (HP) eradication (HPE) therapy on early-stage gastric diffuse large B-cell lymphomas (DLBCLs)
[102]
Helicobacter pylori Therapy in Early-Stage Gastric High-Grade ...
Conclusions: Anti– H. pylori therapy may be considered as one of the treatment options for early-stage H. pylori –positive gastric DLBCL(MALT), and large-scale ...
[103]
Helicobacter pylori-related diffuse large B-cell lymphoma of ... - Nature
Jun 20, 2014 · HP-related gastric 'pure' DLBCL may be a distinct tumor entity, which is less aggressive, and responds better to conventional chemotherapy.
[104]
The biology and treatment of Epstein-Barr virus-positive diffuse large ...
Jan 15, 2024 · Epidemiology and clinical manifestations of EBV+DLBCL-NOS. The proportion of EBV positive rate in DLBCL is relatively higher (8.7%–11.4%) in ...1. Introduction · 5. Diagnosis And... · 7. New Treatment Regimens
[105]
Epstein-Barr virus-associated diffuse large B-cell lymphoma - PubMed
Epstein Barr Virus (EBV)-positive diffuse large B cell lymphoma (DLBCL) most frequently affects elderly patients, without previous immunosuppression.
[106]
Molecular profiling of EBV associated diffuse large B-cell lymphoma
Jan 5, 2023 · EBV positive (EBV+) DLBCL is a rare aggressive B-cell lymphoma subtype with the majority of lymphoma cells being infected by EBV [3]. In Western ...