Definition/General
Introduction:
Diffuse Large B-Cell Lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults
It accounts for 30-40% of all NHL cases
It is characterized by large B-lymphoid cells >2x normal lymphocyte size
It shows diffuse growth pattern obliterating normal architecture.
Origin:
Originates from mature B-cells at various differentiation stages
May arise de novo (primary) or from transformation of indolent lymphomas
Transformation from follicular lymphoma occurs in 30% of cases
Can arise from germinal center or post-germinal center B-cells
Represents clonal proliferation of large B-cells.
Classification:
WHO classification: DLBCL, NOS (not otherwise specified)
Germinal Center B-cell (GCB) type (40%)
Activated B-cell (ABC) type (50%)
Unclassified type (10%)
Molecular subtypes based on cell of origin
Multiple specific variants recognized.
Epidemiology:
Median age 60-70 years
Male predominance (M:F = 1.4:1)
Incidence increases with age
Higher in immunocompromised patients
Geographic variation with higher rates in developed countries
Most common lymphoma requiring urgent treatment.
Clinical Features
Presentation:
Rapidly enlarging lymphadenopathy (60-70% cases)
Extranodal involvement in 30-40% at presentation
B-symptoms in 30% (fever, night sweats, weight loss)
Superior vena cava syndrome possible
Oncologic emergency potential.
Symptoms:
Painless lymphadenopathy (most common presentation)
B-symptoms: fever >38°C, drenching night sweats, weight loss >10%
Abdominal pain and distension
Dyspnea (mediastinal involvement)
Neurologic symptoms (CNS involvement)
Performance status often compromised.
Risk Factors:
Immunosuppression (HIV, organ transplant, autoimmune disorders)
EBV infection (immunocompromised patients)
H
pylori infection (gastric DLBCL)
Chronic inflammation
Previous chemotherapy or radiation
Age >60 years
Male gender.
Screening:
No routine screening available
Diagnosis requires tissue biopsy
Staging with CT/PET scans
Bone marrow biopsy if indicated
Lumbar puncture for high-risk CNS involvement
Flow cytometry and cytogenetics important.
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Gross Description
Appearance:
Enlarged lymph nodes with effaced architecture
Cut surface shows homogeneous gray-white to tan appearance
Soft to firm consistency
Areas of necrosis may be present
Fish-flesh appearance characteristic.
Characteristics:
Lymph node size typically >2 cm
Complete loss of normal architecture
Extracapsular extension common
May form confluent masses
Necrosis in rapidly growing tumors
Hemorrhage occasionally present.
Size Location:
Can involve any lymph node group
Cervical, axillary, mediastinal nodes commonly affected
Abdominal and retroperitoneal nodes frequent
Extranodal sites: GI tract (most common), CNS, bone, liver, kidney
Waldeyer ring involvement.
Multifocality:
Often multifocal at presentation
Tendency for contiguous spread
Extranodal spread common (30-40%)
CNS involvement in high-risk cases
Bilateral involvement possible
Multiple organ involvement in advanced stages.
Microscopic Description
Histological Features:
Diffuse effacement of normal architecture
Large lymphoid cells >2x normal lymphocyte size
High mitotic rate (>10/hpf typical)
Scattered apoptotic bodies
Tingible-body macrophages creating starry-sky pattern
Necrosis in aggressive cases.
Cellular Characteristics:
Large cells with vesicular nuclei and prominent nucleoli
Abundant basophilic cytoplasm
Nuclear size >normal macrophage nucleus
Pleomorphic nuclear features
Frequent mitotic figures
Occasionally multinucleated cells.
Architectural Patterns:
Diffuse growth pattern obliterating normal architecture
May show vague nodular areas
Interfollicular pattern possible
Sclerosis in some cases
Angiocentric pattern occasionally
Cohesive sheets of large cells.
Grading Criteria:
High-grade lymphoma by definition
Mitotic rate typically >10/hpf
Ki-67 proliferation index usually >40%
Starry-sky pattern may be present
Apoptotic rate correlates with grade
No formal grading system applied.
Immunohistochemistry
Positive Markers:
CD20 positive (>95% cases)
CD79a positive (pan-B-cell)
PAX5 positive (B-cell transcription factor)
CD10 positive (GCB type, 40%)
BCL6 positive (70-80%)
MUM1/IRF4 positive (ABC type, 50%).
Negative Markers:
CD3 negative (T-cell marker)
CD5 negative (except rare variants)
CD23 negative
TdT negative (precursor marker)
CD34 negative
ALK negative (except rare ALK+ variant).
Diagnostic Utility:
CD20 positivity confirms B-cell origin
Cell of origin classification crucial: GCB vs ABC type
GCB type: CD10+ and/or BCL6+/MUM1-
ABC type: CD10-/BCL6-/MUM1+ or BCL6+/MUM1+
Therapy selection increasingly based on subtype.
Molecular Subtypes:
GCB type (40%): better prognosis, CD10+, BCL6+
ABC type (50%): worse prognosis, MUM1+, CD138+
Unclassified type (10%): intermediate features
Molecular profiling increasingly replacing immunohistochemistry
Gene expression signatures most accurate.
Molecular/Genetic
Genetic Mutations:
MYC translocations (15% cases, t(8;14) most common)
BCL2 translocations (20% cases, t(14;18))
BCL6 translocations (30% cases)
TP53 mutations (25% cases)
CREBBP/EP300 mutations (histone acetylation)
PRDM1 mutations (ABC type).
Molecular Markers:
Gene expression profiling distinguishes GCB vs ABC
MYC/BCL2 double-hit lymphomas (poor prognosis)
BCL2 protein expression variable (50-60%)
MYC protein overexpression
Complex karyotype common
Chromosomal instability.
Prognostic Significance:
Cell of origin most important: GCB better than ABC
Double/triple-hit lymphomas worst prognosis
MYC overexpression associated with poor outcome
TP53 mutations predict chemotherapy resistance
TMEM30A mutations better prognosis
International Prognostic Index incorporates clinical factors.
Therapeutic Targets:
CD20-targeted therapy (rituximab standard)
BTK inhibitors for ABC type (ibrutinib)
BCL2 inhibitors (venetoclax)
CAR-T cell therapy for relapsed disease
Checkpoint inhibitors under investigation
Targeted agents based on molecular profile.
Differential Diagnosis
Similar Entities:
Burkitt lymphoma (uniformly high Ki-67, MYC+)
Primary mediastinal B-cell lymphoma (mediastinal mass, CD30+)
Follicular lymphoma grade 3 (follicular pattern)
Classical Hodgkin lymphoma (Reed-Sternberg cells)
Anaplastic large cell lymphoma (ALK+)
Reactive hyperplasia.
Distinguishing Features:
DLBCL: CD20+, variable Ki-67, large cells
Burkitt: CD10+, Ki-67 >95%, MYC rearrangement
PMBCL: CD30+, mediastinal location, young females
Hodgkin: CD15+, CD30+, CD20-
ALCL: CD30+, ALK+, anaplastic morphology
Reactive: polymorphous, preserved architecture.
Diagnostic Challenges:
Distinction from Burkitt lymphoma (intermediate morphology)
Recognition of transformed follicular lymphoma
Primary vs secondary CNS involvement
Double-hit lymphomas identification
Composite lymphomas
T-cell/histiocyte rich variants.
Rare Variants:
Primary CNS DLBCL (brain/eye involvement)
Primary cutaneous DLBCL, leg type
Intravascular DLBCL
Plasmablastic lymphoma (HIV-associated)
ALK-positive DLBCL
HHV8-positive DLBCL
DLBCL with IRF4 rearrangement.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
[lymph node/tissue], measuring [size] cm in greatest dimension
Diagnosis
Diffuse Large B-Cell Lymphoma, NOS
WHO Classification
DLBCL, NOS, [GCB/ABC/Unclassified] type based on cell of origin
Histological Features
Shows diffuse proliferation of large B-lymphoid cells with effacement of normal architecture
Immunohistochemistry
CD20 (+), CD79a (+), PAX5 (+), CD10 [+/-], BCL6 [+/-], MUM1 [+/-]
Cell of Origin Classification
Cell of origin: [Germinal Center B-cell/Activated B-cell/Unclassified] type
Proliferation Index
Ki-67 proliferation index: [X]% (high-grade)
Special Studies
FISH: MYC [result], BCL2 [result], BCL6 [result] if performed
Flow cytometry: [results if performed]
Molecular studies: [gene expression profiling if performed]
Prognostic Factors
Cell of origin: [type], IPI score: [if known], Double-hit status: [if tested]
Final Diagnosis
Diffuse Large B-Cell Lymphoma, NOS, [GCB/ABC] type