Diffuse Large B-Cell Lymphoma

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Continuing Education Activity

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma, accounting for about 25% to 30% of all the non-Hodgkin lymphomas. It typically presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extranodal site. Though aggressive, they do respond well to six cycles of rituximab along with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This activity reviews the evaluation and treatment of DLBCL and highlights the role of the interprofessional team in evaluating and treating patients with this condition.


  • Describe the pathophysiology of the B cell lymphomas.
  • Review the workup of the patients with lymphoma.
  • Outlines the treatment of B cell lymphomas, as it depends not only on their staging but also on the type of the disease (indolent or aggressive) and the molecular subtype.
  • Summarize the role of the interprofessional team members in optimizing collaboration and communication to ensure patients with DLBCL receive high-quality care, which will lead to better outcomes.


Lymphoma is the malignancy of the lymphocytes in the lymphoid system, and they can arise from B lymphocytes or T lymphocytes or the natural killer (NK) cells during their different stages of maturation. It can be classified into Hodgkins and Non-Hodgkins lymphoma (NHL). NHL constitutes about 80% of all lymphomas. B- cells are known to have functional diversity and property to transform into multiple pathways.[1] Due to its functional diversity, it represents a heterogeneous group of diseases varying clinically and pathologically. More than 30 subtypes of NHL have been identified, and the common ones are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).[2]


The B cell lymphomas result from the malignant proliferation of B cells during their various stages of development. Depending on the morphology, genetics, and immunophenotype of the neoplastic cells, a cell of origin (COO) is proposed. The development of B cells can be categorized into 3 stages- pre-germinal, germinal, and post-germinal center. Most of the B- cell lymphomas are derived from the germinal center. Like any other malignancy, B cell lymphomas can result from the genetic mutations affecting the proto-oncogenes and tumor suppressor genes; however, the environment within the lymph nodes can also promote lymphomagenesis.[3]

Genetic alterations in the BCL6 gene can be seen in 20% to 40% of the patients. Chronic immunodeficiency of T cells and B cell stimulation can be the possible cause for NHL in human immunodeficiency virus (HIV) infected patients. Certain infectious agents can directly manipulate the DNA, as seen in Burkitt's lymphoma, where the Epstein Barr virus DNA is transported into the B cell nucleus, thus altering the B cell growth and development.[4] HIV is a risk factor for neoplasm development, as it decreases the hosts' ability to regulate malignant cells.

Likewise, an immunosuppressive medication used in transplant patients is a risk factor for the development of B-cell lymphomas. Also, the transformation from different kinds of lymphomas, including splenic marginal zone lymphoma, marginal zone (MALT) lymphoma, chronic lymphocytic leukemia (Ritcher transformation), can result in DLBCL. Other risk factors for the development of B-cell lymphomas include family or personal history of lymphoma, history of radiation, and chemotherapy. Chemical agents such as dyes and pesticides can also increase the risk for lymphoma. Non-Hodgkin lymphoma (NHL) is more common in obese and patients with an underlying history of autoimmune diseases.[5][6]


The incidence of non-Hodgkin lymphoma in the United States is approximately 7 cases per 100,000 per year.[7] DLBCL accounts for about 25% of all NHL cases worldwide. DLBCL is the most common NHL, followed by FL.[8] The disease occurs more frequently in whites, followed by African Americans and Asians with male preponderance and a median age of 64 years. The overall incidence increases exponentially with age.


To better understand the molecular diversity among morphologically similar variants of DLBCL, high throughput technology such as gene expression profiling (GEP) could classify DLBCL into germinal center B-cells (GCB) and activated B-cells (ABC). Most of the patients with DLBCL show gene rearrangements in the heavy and light chains of the immunoglobulin. About 80% of DLBCL expresses B cell leukemia or lymphoma 2 (BCL2) protein, and 70% expresses B cell lymphoma 6 (BCL6) protein.[9] Some of them also express abnormalities in the gene MYC. The flow cytometry reveals CD19, CD20, CD22, CD45 and CD79a. CD30 can be seen in 25% and carries a favorable prognosis. Very rarely, they can express CD5, which has a poor prognosis.[10]

More than 50% of the DLBCL expresses surface or cytoplasmic immunoglobulin IgM. Double hit lymphoma presents like DLBCL but has MYC along with BCL2 and/or BCL6. A triple hit lymphoma has rearrangements in BCL2, BCL6, and MYC. The (14;18) translocation is related to disseminated and nodal disease and does not imply a poor prognosis. The t(14:18) is seen in more than 90% of FL and about 30% of DLBCL patients. DLBCL commonly involves extranodal sites, which include the brain, bones, kidneys, adrenal glands, and other soft tissues.[11] 

Pathophysiology of non-Hodgkin B cell lymphomas is dependent on the type of lymphoma. B cell lymphomas are categorized based on the stage of B cell development that has resulted in malignancy (i.e., mantle cell vs. marginal cell lymphoma). Lymphadenopathy occurs due to the proliferation of B cells in or around the germinal center. Systemic symptoms (B-symptoms) are due to increased cytokine production. Elevated levels of LDH and uric acid suggest high cell turnover and release of degradation products into the bloodstream. 


The normal architecture of lymph nodes is distorted and is replaced by sheets of atypical lymphoid cells with large nuclei, basophilic cytoplasm, and high proliferation rate.

History and Physical

Most of the NHL spread hematogenously, whereas Hodgkin lymphoma disseminates via the lymphatic spread. Due to the hematogenous spread, most present with advanced disease (stage III or IV). A whole-body lymphoid survey should be performed, including the head, neck, cervical, supraclavicular, axillary, mesenteric, femoral, and inguinal lymph nodes. An abdominal examination should be performed to evaluate for enlarged liver and spleen. DLBCL commonly presents with enlarged lymph nodes or rapidly growing mass along with B symptoms, which include fever, night sweats, and weight loss. The B symptoms can be seen in 30% of the patients. Bone marrow involvement is more common in indolent disease and can be seen in up to 50% of the cases.[12]

About 50% of the patients have extranodal involvement. The involvement of the stomach or gastrointestinal tract is the most common primary extranodal site, followed by the involvement of the skin. Renal involvement can be secondary to bulky disease or lymphadenopathy, causing a ureteral obstruction or due to tumor lysis syndrome. Extralymphatic involvement is seen in aggressive NHL. DLBCL can also present with symptoms suggestive of superior vena cava syndrome, compression of the airways. The symptoms can be related to the infiltrated organ if the disease spreads beyond the lymphatics in so-called extranodal disease. The extranodal disease can manifest in the skin, bones, spinal cord, testicles, among other locations. A variety of paraneoplastic syndromes may also be associated with B cell lymphomas.[13]

The presentation of B cell lymphomas varies based on if the subtype behaves aggressively or is more indolent. The aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma and Burkitt’s lymphoma, typically present with a rapidly growing mass. Epidural spinal cord compression can be the manifestation of NHL or can happen at the time of relapse.[14] Indolent lymphomas like FL and marginal zone lymphoma develop over time, and history reveals intermittent or progressive lymphadenopathy. FL typically presents with painless lymphadenopathy and near-normal LDH levels.


A detailed clinical and physical examination and the laboratory and imaging studies are essential for the diagnosis of lymphoma. Laboratory data include Complete blood count with differential (CBC), comprehensive metabolic profile (CMP), lactate dehydrogenase (LDH), HIV and Hepatitis B and C serologies, and serum protein electrophoresis. CBC can show cellular atypia on smears as well as cytopenias. Patients with symptoms or at risk of central nervous system (CNS) involvement should have a lumbar puncture. HIV should be tested as B cell lymphomas can be an AIDS-defining illness. Besides, as the treatment involves significant immunosuppression, it requires consideration of the patient’s HIV and hepatitis status. Renal involvement can be seen by up to 14% of the patients. LDH is elevated in more than 50% of the cases. LDH is a predictor of survival.[15]

Excisional biopsy of the lymph node is preferred over fine-needle aspiration (FNA) to look for the entire architecture of the node along with the histologic and immunologic studies. The morphology and immunophenotyping, along with staining for B-cell markers, are needed for the diagnosis. Imaging of choice includes positron emission tomography (PET) and computed tomography (CT) for staging the disease. PET is useful in most B cell lymphomas, as the sites with high standardized uptake value (SUV) may indicate aggressive disease. PET scan is less useful in CLL, as it is fluoro-deoxyglucose (FDG) nonavid.[16] Along with staging, imaging can assist in finding the least invasive site for diagnostic biopsy. In the absence of significant lymphadenopathy, tissue sampling of the involved organs should be considered. 

Treatment / Management

The treatment of B cell lymphomas depends not only on their staging but also on the type of the disease (indolent or aggressive) and the molecular subtype. Though DLBCL is aggressive, with appropriate chemotherapy, the survival can be long, but with a limited cure rate. Patients with GCB DLBCL respond well to 6 cycles of rituximab along with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen given every 21 days.[17][18] Rituximab is an anti-CD20 monoclonal antibody and administered intravenously at 375 mg/m2 on day one of chemotherapy. ABC DLBCL, along with double-hit and triple hit lymphomas, had poor outcomes with R-CHOP.

Studies have shown that patients with ABC DLBCL be enrolled in clinical trials, and the use of R-CHOP along with lenalidomide or bortezomib or ibrutinib is indicated. The more aggressive approach is rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP), followed by consolidation with methotrexate and leucovorin.[19] Studies have suggested using six to eight cycles of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) in patients with advanced double hit DLBCL. Intravenous rituximab therapy has become the backbone for the treatment of indolent lymphomas. Other regimens include (R-CHOP); bendamustine or cyclophosphamide, doxorubicin, and prednisone (R-CVP).

The treatment for indolent lymphomas such as follicular lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma often depends upon the bulk of the disease and in symptomatic cases. Some patients with the aggressive low-grade disease have been treated with allogeneic transplants with curative intent. Radiotherapy should be considered in patients with bulky disease. Mantle cell lymphomas are treated aggressively with immuno-chemotherapy and autologous stem cell transplants. Burkitt lymphoma and lymphoblastic lymphoma are considered high grade and need aggressive chemotherapy along with prophylactic intrathecal chemotherapy.

Differential Diagnosis

The differential diagnoses include infectious mononucleosis, Hodgkin lymphoma, T-cell lymphomas, and other large cell malignancies such as carcinomas, melanoma, and Kikuchi disease. Melanomas can also involve the lymph nodes but can be differentiated from DLBCL by positive S100, HMB-45, and Melan A staining.

Toxicity and Adverse Effect Management

  • Infection risk
  • Febrile neutropenia
  • Reactivation of hepatitis
  • Progressive multifocal leukoencephalopathy


Originally, the Ann Arbor staging system was introduced for Hodgkin's lymphoma in 1974 and later modified in 1988. The current staging system Lugano classification is based on the Ann Arbor classification.[20]A single lymph node region is a node or group of adjacent nodes.

  • Stage I - NHL involving one lymph node region or extra lymphatic site
  • Stage IE - Involvement of single extra lymphatic site involvement. "E" stands for limited extranodal involvement.
  • Stage II - Involving two or more lymph nodes on the same side of the diaphragm
  • Stage III - Involving lymph nodes on both the sides of the diaphragm
  • Stage IV - Spreads into one or more extra-lymphatic organs (bone marrow, liver, lung) with or without the involvement of the lymph node.


Overall, the prognosis of NHL is dependent on the staging of the disease, histopathology, extranodal involvement, age, and performance status. Treatment response is monitored by clinical examination, laboratory values, and imaging studies. The international prognostic index (IPI) can be used for prognostification in DLBCL. Age more than 60 years, Eastern Cooperative Oncology Group (ECOG) performance greater than 2, LDH elevated, clinical-stage III/IV, and more than 1 extranodal involvement correlates with decreased overall survival (OS).

DLBCL is an aggressive disease that can be cured in up to 50% of the patients who achieve a complete remission following treatment with first-line therapy. GCB cell type has a better prognosis compared to the ABC type. Double hit and triple hit lymphomas carry a poor prognosis when compared to DLBCL.


  • Involvement of bone marrow leading to cytopenias and increased risk of infection. 
  • Renal failure
  • CNS involvement


  • Medical oncology
  • Radiation oncology

Deterrence and Patient Education

Among NHL, DLBCL is the most common subtype accounting for about 25% to 30% of all cases worldwide. It most commonly presents with a rapidly growing mass or enlarging lymph nodes in a nodal or extranodal site. Though aggressive, it responds well to chemotherapy.

Enhancing Healthcare Team Outcomes

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma,  accounting for about 25% to 30% of all non-Hodgkin lymphoma. This disease presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extranodal site. Though aggressive, it does respond well to chemotherapy. It can affect many organ systems and is best managed by an interprofessional team, including the medical oncologist, radiation oncologist, and nephrologists. Radiation therapy can be needed in extranodal lymphomas.

Kidney involvement has been well documented in patients with lymphoma. It is important to get the nephrologist involved early in the course of the disorder as renal failure is a complication of DLBCL itself, or renal failure can manifest during treatment. Careful assessment of the renal indices, including acid-base, electrolytes, and volume status, should be assessed.



Avyakta Kallam


4/24/2023 12:37:39 PM



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