Diffuse Large B Cell Lymphoma: Symptoms, Types, Causes and Treatment

Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, representing a highly diverse and complex disease. Its rapid progression, variable symptoms, and evolving treatment landscape make it a uniquely challenging yet hopeful area in cancer care. This article will guide you through the essential aspects of DLBCL, from how it manifests and the different forms it can take, to what causes it and how it is treated today.

Symptoms of Diffuse Large B Cell Lymphoma

DLBCL often presents with a wide array of symptoms, ranging from subtle changes to severe organ dysfunction. Because it can arise in both lymph nodes and almost any organ in the body, its symptoms are highly variable and sometimes misleading. Early recognition and accurate diagnosis are crucial, as timely treatment significantly impacts prognosis.

Symptom	Description	Common Sites/Contexts	Source(s)
Swelling	Painless, rapidly growing mass	Lymph nodes, jaw, oral cavity	2 3
B symptoms	Fever, night sweats, weight loss	Systemic	3
Numbness	Hypoesthesia, paresthesia	Chin, lip, face, cranial nerves	1 2
Organ dysfunction	Symptoms related to specific organs	CNS, kidneys, heart, GI tract	4 5 3
Skin changes	Erythematous plaques, indurations	Face, skin	1
Fatigue	Generalized weakness	Systemic	3

Table 1: Key Symptoms

Understanding the Symptom Spectrum

Classic Symptoms

The most frequent initial sign is a painless, rapidly enlarging mass, often in a lymph node. In some cases, swelling may be found in less typical places such as the jaw or oral cavity, especially when DLBCL starts outside lymph nodes (extranodal) 2 3. Systemic symptoms—referred to as "B symptoms"—include unexplained fever, drenching night sweats, and unintentional weight loss. These are common in advanced disease and signify a more aggressive course 3.

Neurological and Sensory Symptoms

DLBCL can invade nerves, leading to numbness, tingling (paresthesia), or even facial paralysis, especially if the cranial nerves are involved. For example, involvement of the facial or trigeminal nerves can result in numbness of the chin, lip, or one side of the face 1 2. These neurological symptoms can precede more obvious signs like swelling and are sometimes mistaken for other conditions.

Organ-Specific Manifestations

Because DLBCL can involve almost any organ, symptoms vary widely:

• Central nervous system (CNS): Headache, blurred vision, seizures, or weakness on one side of the body if the brain is affected 5.
• Kidneys and heart: Rare but serious, leading to acute kidney injury or cardiac arrhythmias 4.
• Gastrointestinal tract: Abdominal pain, bleeding, or obstruction if the GI tract is involved 3.

Skin and Soft Tissue

Sometimes, DLBCL appears as red, indurated (hardened) plaques on the skin, often accompanied by underlying muscle involvement and destruction 1.

Fatigue

Generalized tiredness and malaise are common but non-specific, often accompanying the other symptoms above 3.

Types of Diffuse Large B Cell Lymphoma

DLBCL is not a single disease, but a collection of biologically and clinically distinct subtypes. These subtypes differ in their genetic makeup, cell of origin, and response to treatment, making accurate classification critical for optimal care.

Type/Subtype	Defining Features	Prognosis/Treatment Implications	Source(s)
Germinal Center B-cell-like (GCB)	Originates from germinal center B cells; distinct gene expression	Better prognosis with standard therapy	6 7 8
Activated B-cell-like (ABC)	Originates from activated peripheral B cells; different gene profile	Worse prognosis, may need targeted therapy	6 7 8 11
Primary Extranodal DLBCL	Arises outside lymph nodes (e.g., CNS, GI, skin)	Site-specific symptoms and treatment	3 5 1 2
Genetic Subtypes (MCD, BN2, N1, EZB)	Defined by recurrent genetic mutations and fusions	Varying outcomes, enable precision medicine	7 8 12
Double/triple hit lymphoma	Rearrangement of MYC, BCL2, and/or BCL6 genes	Very aggressive, requires intensive regimens	10 16

Table 2: Main Types of DLBCL

Molecular and Cellular Subtypes

Cell-of-Origin Classification

• Germinal Center B-cell-like (GCB):

  • Arises from B cells in the germinal centers of lymph nodes.
  • Characterized by specific gene expression patterns.
  • Generally has a better outcome with standard treatments like R-CHOP 6 7 8.

• Activated B-cell-like (ABC):

  • Comes from more mature B cells activated outside the germinal center.
  • Exhibits distinct gene activation, including continuous NF-κB pathway activation.
  • Typically has a poorer prognosis and may require novel, targeted therapies 6 7 8 11.

Genetic Subtypes

Recent genetic profiling has uncovered further subdivisions based on shared genetic mutations:

• MCD: MYD88 and CD79B mutations. Associated with chronic active B-cell receptor signaling.
• BN2: BCL6 fusions and NOTCH2 mutations. Generally better prognosis.
• N1: NOTCH1 mutations. Poorer outcomes.
• EZB: EZH2 mutations and BCL2 translocations; favorable prognosis 7 8 12.

These genetic distinctions are paving the way for personalized medicine in DLBCL.

Other Notable Subtypes

• Double/triple hit lymphoma: Characterized by rearrangements in MYC, BCL2, and/or BCL6 genes. Highly aggressive and requires more intensive treatment regimens 10 16.
• Primary extranodal DLBCL: Can arise in places like the CNS, GI tract, skin, or bones, each with unique symptoms and treatment needs 3 5 1 2.

Clinical and Site-Specific Variants

• Primary CNS DLBCL: Presents with neurological symptoms, poor prognosis 5.
• Primary cutaneous DLBCL: Causes localized skin lesions, sometimes better outcomes 1.
• Plasmablastic lymphoma: Lacks CD20 expression, does not benefit from rituximab 17.

Causes of Diffuse Large B Cell Lymphoma

DLBCL arises from a complex interplay of genetic, molecular, and environmental factors. Understanding its causes not only helps in unraveling disease mechanisms but also in developing new treatment approaches.

Cause/Factor	Mechanism/Role	Key Details	Source(s)
Genetic mutations	Alter key signaling pathways	Affect NF-κB, BCR, Wnt, apoptosis	11 12 13 14
Chromosomal translocations	Disrupt gene regulation	Involve MYC, BCL2, BCL6 (double/triple hit)	13 10
Viral infections	Promote B cell transformation	EBV (Epstein-Barr virus) linked in some cases	15
Epigenetic changes	Alter gene expression	Impact differentiation and proliferation	13 12
Environmental/Unknown	Not fully defined	Possibly immune suppression, chronic inflammation	13 16

Table 3: Key Causes of DLBCL

Genetic and Molecular Drivers

Mutations and Signaling Pathways

DLBCL is driven by mutations affecting a range of signaling pathways:

• NF-κB Pathway: Frequently activated in ABC-DLBCL due to mutations in genes like TNFAIP3 (A20), CARD11, TRAF2, and others. This leads to uncontrolled cell survival and proliferation 11 13.
• B-cell Receptor (BCR) Signaling: Sustained activation through mutations (e.g., CD79B) promotes tumor growth and survival 7 13.
• Wnt/β-catenin Pathway: Upregulated via non-coding RNAs (like OR3A4) and transcription factors (FOXM1), contributing to DLBCL progression 14.
• PI3K/AKT/mTOR Pathway and Others: Additional mutations (e.g., in PIK3CD, MTOR) further contribute to DLBCL’s genetic heterogeneity 12 13.

Chromosomal Translocations

Structural changes in chromosomes, particularly involving MYC, BCL2, and BCL6, result in highly aggressive forms ("double/triple hit lymphoma") 10 13.

Viral and Environmental Factors

• Epstein-Barr Virus (EBV): Plays a role in some DLBCL cases, particularly in immunosuppressed individuals or specific subtypes, by driving B cell transformation 15.
• Immunodeficiency and Chronic Inflammation: Both may increase risk, though precise environmental triggers remain incompletely understood 13 16.

Epigenetic Changes

Alterations in histone modifiers and DNA methylation genes (e.g., ARID1A, EZH2) affect B cell differentiation, further promoting lymphoma development 12 13.

Treatment of Diffuse Large B Cell Lymphoma

DLBCL is one of the few aggressive lymphomas that can be cured, especially when diagnosed early and treated appropriately. The treatment landscape is rapidly evolving, with both established regimens and exciting new therapies coming into play.

Treatment	Approach/Medication	Best Use Cases	Source(s)
R-CHOP	Rituximab + CHOP chemotherapy	Standard frontline therapy	9 16 18 19 20
Radiotherapy	Localized radiation	Early-stage or bulky disease	9
CAR-T cell therapy	Genetically modified T cells	Relapsed/refractory DLBCL	18 20
Targeted therapies	e.g., polatuzumab, venetoclax, tafasitamab, lenalidomide	Relapsed/refractory; molecular subtypes	18 20
Bispecific antibodies	Engage T cells and tumor cells	Relapsed/refractory DLBCL	18 20
High-dose therapy with stem cell transplant	Intensive therapy + stem cell rescue	Select relapsed/young patients	16 18 20

Table 4: Main Treatment Approaches for DLBCL

Standard and Frontline Therapies

R-CHOP: The Gold Standard

R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is the backbone of DLBCL treatment. This regimen cures approximately two-thirds of patients 9 16 18 19 20. The addition of rituximab to CHOP has improved survival outcomes across age groups 9.

• Localized DLBCL: May receive abbreviated R-CHOP cycles plus radiotherapy 9.
• Bulky or advanced disease: Standard R-CHOP is the first-line treatment 9 16 19.

Novel and Emerging Therapies

CAR-T Cell Therapy

Chimeric antigen receptor T-cell (CAR-T) therapy is revolutionizing the treatment of relapsed or refractory DLBCL, offering durable responses in patients who have failed multiple lines of therapy 18 20.

Targeted and Biologic Agents

• Polatuzumab vedotin: Antibody-drug conjugate targeting CD79b, used in combination with R-CHP or other agents 18 20.
• Venetoclax: BCL2 inhibitor, promising in molecularly defined subtypes 18.
• Tafasitamab + lenalidomide: For patients ineligible for stem cell transplant 18.
• Bispecific antibodies: New agents that engage both T cells and lymphoma cells for targeted killing 18 20.

Site-Specific and Subtype-Tailored Therapy

Some DLBCL subtypes, such as those arising in the CNS or those lacking CD20, require distinct approaches:

• CNS DLBCL: High-dose methotrexate-based regimens 5 17.
• Plasmablastic lymphoma: Does not benefit from rituximab, needs alternative chemotherapy 17.
• Double/triple hit lymphoma: Often treated with more intensive regimens than R-CHOP 10 16.

The Move Toward Precision Medicine

Genetic and molecular profiling is increasingly guiding therapy choice, with new trials investigating tailored regimens based on molecular subtype and genetic abnormalities 7 8 18 20. As our understanding of DLBCL's heterogeneity grows, so does the potential for more effective, personalized treatments.

Conclusion

Diffuse large B cell lymphoma is a diverse and aggressive cancer, but advances in our understanding, diagnosis, and treatment are steadily improving patient outcomes. Here’s a summary of key points:

• Symptoms: DLBCL presents with painless swelling, B symptoms (fever, night sweats, weight loss), neurological changes, and organ-specific symptoms depending on disease location [1-5].
• Types: Includes molecular subtypes such as GCB and ABC, genetic subtypes (MCD, BN2, N1, EZB), primary extranodal forms, and aggressive double/triple hit lymphomas [6-8,10,12,16,17].
• Causes: Driven by a complex interplay of genetic mutations, chromosomal translocations, viral factors (EBV), and epigenetic alterations [11-15].
• Treatment: R-CHOP remains the standard, but novel therapies such as CAR-T, targeted agents, and bispecific antibodies are transforming care, with precision medicine on the horizon [9,16,18-20].

Staying informed about DLBCL’s evolving landscape empowers patients, families, and clinicians to seek the best possible outcomes.