Diffuse Large B-cell Lymphoma (DLBCL) is one of the most common forms of Non-Hodgkin Lymphoma (NHL) in adults throughout the world. This is an aggressive cancer that originates from B lymphocytes, the type of white blood cell that produces antibodies to help the body fight off infection. In DLBCL, the B cells grow uncontrollably and form tumors in lymph nodes or elsewhere in the body, depending on where it occurs. 

As is the name, the cancer involves large malignant B cells that appear “diffuse,” or widely scattered, when viewed on a microscope. DLBCL is known as high-grade (fast growing) blood cancer compared to some slow-growing lymphomas described in prior chapters. As such, DLBCL is fast-growing cancer and requires prompt diagnosis and treatment. Despite being a fast-growing cancer, of all forms of lymphoma, it is easily one of the most treatable and curable when treated appropriately and in a proper timeframe.

Moreover, DLBCL can occur as either a new (primary) cancer or as a transformation from pre-existing, slow-growing lymphoma, particularly follicular lymphoma. DLBCL can affect people of all ages although it is primarily seen in adults, as well as older adults over the age of 60 (although many younger adults and children can develop DLBCL). DLBCL can develop throughout the body and not simply in the lymph nodes (including the stomach, brain, liver, skin and bones).

While the precise origin of diffuse large B-cell lymphoma (DLBCL) is not known, researchers have identified several exposures and conditions that may contribute to the development of DLBCL: 

1. Genetic Alterations: DLBCL typically develops when B cells experience genetic alterations leading to uncontrolled growth and division. These types of genetic changes can impact normal cellular growth, cellular survival, or cellular death (apoptosis) related genes.
2. Weakened Immune Systems (Immunosuppression): People with impaired immune systems have a higher risk of developing DLBCL. For example, this includes people who are: Living with HIV/AIDS; under immunosuppressive therapy for organ transplantation; have genetic immune deficiencies.
3. Infections: Several viral infections and bacterial infections have been linked to DLBCL:
   • Epstein-Barr Virus (EBV): Frequently associated with DLBCL in individuals with impaired immune systems. 
   • Hepatitis C Virus (HCV): May promote lymphoma development in its own right, and may increase lymphoproliferative disorders.
   • Helicobacter pylori: Gastric bacteria, which has been linked to some forms of gastric lymphomas including the subset of DLBCL.
4. Autoimmune Diseases: Chronic autoimmune diseases like rheumatoid arthritis, lupus and Sjögren’s syndrome may also increase the risk for lymphoma as a result of sustained inflammation or chronic engagement of the immune system.
5. Environmental Exposure: Environmental exposure to chemicals such as pesticides, herbicides and industrial solvents has been correlated with incidence of lymphoma. While the relationship has yet to be established, the evidence continues to emerge.
6. Age and Gender: DLBCL primarily occurs in older adults (mostly males) but they may also appear at any age in any gender.

Diffuse large B-cell lymphoma (DLBCL) occurs when a normal B lymphocyte, which are white blood cells that fight infection, experiences genetic changes resulting in uncontrolled and excessive growth. This causes the abnormal cells to accumulate over time in lymph nodes or in other parts of the body to form tumors.

Often, DLBCL just appears with no known reason. Most people with DLBCL don’t have a systematic cause that can be identified, but there are certain risk factors (e.g. weakened immune system, chronic infections, autoimmune diseases) that can put someone at risk for the developing this type of lymphoma.

In some instances, DLBCL is not the only lymphoma a person has had. DLBCL can develop from a slower-growing type of lymphoma (“follicular lymphoma”). Although this change is somewhat concerning for the patient, it is usually just indicating that the lymphoma has transformed from a slower-growing lymphoma to a faster-growing lymphoma, which may require a different therapeutic approach.

DLBCL can begin in different places than in the lymph nodes. DLBCL can occur in other sites of the body, which are referred to “extranodal sites.” Common virus-specific extranodal sites for DLBCL include the stomach, skin, testicles, thyroid, brain (central nervous system) and bones.

The signs of diffuse large B-cell lymphoma (DLBCL) can vary greatly depending on its location, stage, and whether it has metastasized. Generally, they can be divided into general, or constitutional symptoms and localized symptoms. 

General Symptoms (or “B Symptoms”):

These are the systemic symptoms that are frequently associated with aggressive lymphomas like DLBCL:

• Unexplained, recurrent fever
• Drenching night sweats (often so severe that clothing and sheets are soaked)
• Unintentional weight loss of more than 10% of body weight over six months

These symptoms may indicate more advanced lymphoma, or rapid dissemination, and are present in staging and treatment decisions.

Localized Symptoms:

These symptoms are connected to the body area involved with the lymphoma:

Skin changes: Nodules, lumps or rashes can occur if the lymphoma involves the skin.st from a few minutes to several hours. While the seizure itself typically lasts 1 to 3 minutes, recovery time varies by individual. If a seizure lasts longer than 5 minutes, or if multiple seizures occur without a return to awareness between them, it is known as status epilepticus—a serious medical emergency.

Swollen lymph nodes: These may appear as painless lumps in the neck, underarms or groin. These may have come up suddenly and can present as rapidly growing.

Abdominal discomfort or swelling: This can occur if the lymphoma involves the liver, spleen or intestines then this can happen.

Chest pain, cough or difficulty breathing: These symptoms may develop if the lymph nodes in the chest are enlarged.

Fatigue and overall weakness: These symptoms may result from the immune system’s response to lymphoma or the effects of the disease on the body.

Neurological symptoms: Headaches, seizures or vision problems may occur if the lymphoma has spread to the brain or spinal cord (central nervous system involvement has occurred).

Resolving diffuse large B-cell lymphoma (DLBCL) is done with a combination of obtaining a history, physical examination, imaging, impassioned analysis and laboratory studies. The precise diagnosis is critical in determining therapeutic settings. 

1. Physical Examination: A physician will assess for lymphadenopathy; organomegaly (swelling of liver or spleen), and physical signs of any treatment discussion.
2. Biopsy (Gold Standard): A biopsy can determine not only a diagnosis but also which subtype of lymphoma one has. Types of biopsies include: 
   • Excisional biopsy (preferred unless a surgical and radiographic assessment has been completed that confirms only one node is affected): Will remove the entire lymph node.
   • Core needle biopsy: Utilizing a needle the physician can obtain a sample.
3. Immunohistochemistry and Fluorescence Activated Cell Sorting: Tests that seek specific markers on lymphoma cells such as in the CD20 lymphocyte antigen, are helpful in classifying the lymphoma.
4. Molecular or Genomic Testing: Tests such as HISH (FISH) or polymerase chain reaction (PCR) will evidence with a high degree of accuracy whether there are abnormalities of genetic sequences regarding management of therapeutic options (Examples: BCL2, BCL6, MYC) particularly if all abnormalities were mutually exclusive.  Some cases are referred to as double-hit or triple-hit lymphomas, which when discovered, are inherently more aggressive.
5. Imaging Investigations: Imaging examines extent and spread of the disease:
   • CT scan (chest, abdomen, pelvis)
   • PET-CT scan: More sensitive to active lymphoma
   • MRI scan: Indicated if there is concern for possible involvement in the brain or spine
6. Bone Marrow Biopsy: Determines if lymphoma has extended to the bone marrow, especially in advanced cases.
7. Lumbar Puncture: Indicated in the case of possible central nervous system (CNS) involvement.
8. LDH test (Lactate Dehydrogenase): High LDH may be indication of considerable disease activity.
9. Blood Tests: Include the following:
   • Complete blood cell count (CBC): Red/white blood cells and platelets
   • Liver and kidney functions
   • Screening for infections including HIV and hepatitis, which are potential modifiers of treatment

Diffuse large B-cell lymphoma (DLBCL) is a rapid-growing, potentially curable kind of non-Hodgkin lymphoma. Early detection and appropriate treatment significantly improve survival outcomes. Most importantly, treatment modalities depend on specific features of the lymphoma (molecular and genetic profile), stage of disease, the patient’s age and general health status.

• Chemotherapy (R-CHOP Regimen): The most common first-line treatment is R-CHOP, which consists of chemotherapy and immunotherapy. R-CHOP consists of:
  • Rituximab- a monoclonal antibody against CD20 on B cells
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Prednisone

R-CHOP is usually given in 21-day cycles and is given for six cycles. R-CHOP is very effective and cures 60-70% of patients, particularly when started early.

• Radiation: Radiation is used in certain circumstances when the lymphoma is localized, or bulky disease. Radiation is used after chemotherapy to minimize the chance of disease relapse.
• High-dose Chemotherapy With Stem Cell Transplant: In the case of relapsed or treatment-refractory DLBCL, high-dose chemotherapy with autologous stem cell transplant (using the patient’s own stem cells) recommendations may be advised. Autologous stem cell transplant is often used after second-line chemotherapy fails to adequately control the disease.
• CAR T-Cell Therapy: Chimeric Antigen Receptor (CAR) T-cell therapy offers a new option for patients with relapsed or refractory DLBCL. This therapy involves programming a patient’s T-cells to recognize and kill lymphoma cells. Currently the approved CAR T therapies include:
  • Axicabtagene ciloleucel (Yescarta)
  • Tisagenlecleucel (Kymriah)
• Targeted Therapies: For certain patients, targeted therapies may be offered, which target a specific mutation:
  • Polatuzumab vedotin – antibody-drug conjugate
  • Lenalidomide – immune-modulating agent
  • Ibrutinib – BTK (Bruton’s tyrosine kinase) inhibitor (for some subtypes)
• Clinical Trials: Patients with aggressive, relapsed or refractory DLBCL may be eligible for clinical trials of experimental options including:
  • Bispecific antibodies
  • Checkpoint inhibitors
  • Novel immunotherapies
• Second-Line Therapy and Autologous Transplant: If the DLBCL relapses after R-CHOP, patients may receive second-line chemotherapy (more intense combinations of drugs), followed by an autologous stem cell transplant. This will maximize the chance of remission.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and one of the most treatable. It is an aggressive cancer of B lymphocytes that can be successfully treated if caught early and treated in a timely way. 

Although the precise cause of DLBCL is often unknown, there are several factors that can increase its risk, such as immune system issues, certain infections, or genetic mutations. Symptoms vary from patient to patient, but hallmark signs are painless swollen lymph nodes, fever, night sweats, and unexplained weight loss. 

Typically, diagnosis of DLBCL involves a biopsy, imaging scans, and blood tests to categorize the type and stage of the disease. Treatment is organic and usually consists of the chemotherapy regimen R-CHOP plus or minus radiation or stem cell transplant if complicated. Newer therapies such as CAR T-cell treatment and targeted drugs hold promise for patients with hard-to-treat lymphoma and that may have returned. 

Significant strides have been made in medicine and many patients diagnosed with DLBCL achieve remission and lead full, healthy lives. Research and individualized care will continue to improve DLBCL.

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