[5] 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, weight loss, and night sweats.

[15] Numerous subtypes of DLBCL have been identified which differ in their clinical presentations, biopsy findings, aggressive characteristics, prognoses, and recommended treatments.

[19] Diffuse large B-cell lymphoma encompasses a biologically and clinically diverse set of disease subtypes,[20] many of which are difficult to separate from one another based on well-defined and widely accepted criteria.

[22] The remaining DLBCL cases consist of relatively rare subtypes that are distinguished by their morphology, (i.e. microscopic appearance), immunophenotype, (i.e. expression of certain marker proteins), clinical findings, and/or association with certain pathogenic viruses.

[12] 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.

In general, DLBCL, NOS is an aggressive disease with an overall long-term survival rate in patients treated with standard chemotherapy regimens of ~65%.

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.

[22] 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.

[22] 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.

[27] 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 prophylaxis to reduce the incidence of this complication.

[31] 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.

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 autologous stem cell transplantation.

Chimeric antigen receptor T cell (i.e. CAR-T) adoptive cellular immunotherapy has emerged as a recent advance in treating refractory and relapsed DLBCL, NOS (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel).

The targeted antigen has usually been CD19, a surface membrane protein expressed on virtually all B-cells including the neoplastic cells in DLBCL, NOS.

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.

[36] 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.

[33] As a consequence of these studies, the Committee for Advanced Therapies and the 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.

[22] 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.

[39] 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.

[41] 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, toll-like receptor, and NF-κB signaling pathways.

[22] 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.

[14] CUDC-907, an inhibitor of PI3K and histone deacetylases, is being evaluated in two separate clinical trials[42][43] for the treatment of refractory and/or relapsed DLBCL, NOS including cases with alterations in the MYC gene.

[44] 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 and MCL-1.

[12] 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 differentiated features infiltrate the brain, spinal cord, leptomeninges, or eye.

[24] 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.

[23] Recent studies suggest that localized, early-stage H. pylori+ DLBCL, when limited to the stomach, is successfully treated with H. pylori eradication protocols consisting of two or more antibiotics plus a proton pump inhibitor.