Definition/General
Introduction:
Angioimmunoblastic T-cell lymphoma (AITL) is a aggressive peripheral T-cell lymphoma derived from follicular helper T-cells (TFH)
It represents 15-20% of all peripheral T-cell lymphomas
The disease is characterized by a distinctive morphological pattern with prominent vascularity, clear cells, and follicular dendritic cell proliferation
Systemic symptoms and immunological abnormalities are prominent features
Poor prognosis with median survival 1-3 years.
Origin:
Originates from follicular helper T-cells (TFH) that normally reside in germinal centers
Shows clonal T-cell receptor gene rearrangements
Expresses follicular helper markers (PD1, CXCL13, BCL6, ICOS)
Germinal center microenvironment is disrupted
Epstein-Barr virus (EBV) association in many cases
Somatic mutations in genes involved in T-cell development and function.
Classification:
WHO classification recognizes as distinct T-cell lymphoma subtype
Previously known as angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)
Part of nodal T-cell lymphomas with TFH phenotype
Pattern-based variants recognized but not separately classified
Grade not applicable as uniformly high-grade
Staging follows Ann Arbor system.
Epidemiology:
Peak incidence in 6th-7th decades
Slight male predominance (M:F = 1.2-1.5:1)
Most common T-cell lymphoma in elderly patients
Represents 1-2% of all non-Hodgkin lymphomas
Geographic variation with higher incidence in developed countries
Associated with immunosuppression
Indian population shows similar age and gender distribution.
Clinical Features
Presentation:
Generalized lymphadenopathy (>90% of cases)
Constitutional symptoms prominent (fever, night sweats, weight loss)
Hepatosplenomegaly common (60-80%)
Skin rash (40-50% of cases)
Pleural effusions and ascites
Autoimmune phenomena (hemolytic anemia, thrombocytopenia)
Hypergammaglobulinemia with polyclonal increase.
Symptoms:
B-symptoms in >80% of patients
High fever often hectic pattern
Drenching night sweats
Significant weight loss (>10% body weight)
Skin manifestations (rash, pruritus)
Arthralgia and myalgia
Edema (due to hypoalbuminemia)
Recurrent infections due to immunosuppression.
Risk Factors:
Advanced age (peak 6th-7th decades)
Immunodeficiency states (organ transplant, HIV)
Autoimmune diseases (rheumatoid arthritis, Sjögren syndrome)
EBV infection (may be reactivation)
Previous malignancy (rare association)
Chemical exposures (controversial)
Genetic predisposition (rare familial cases).
Screening:
Complete blood count (cytopenias common)
Comprehensive metabolic panel (liver function, albumin)
LDH elevation (>75% of cases)
Hypergammaglobulinemia with polyclonal pattern
Direct antiglobulin test (Coombs test)
Imaging studies for staging
EBV serology and viral load
Autoimmune markers if indicated.
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Gross Description
Appearance:
Enlarged lymph nodes with loss of normal architecture
Soft to firm consistency
Gray-pink cut surface with prominent vascularity
Tan to yellow areas may be present
Necrosis uncommon
Capsular involvement frequent
Matting of adjacent nodes may occur.
Characteristics:
Fish-flesh appearance with increased vascularity
Homogeneous gray-pink cut surface
Soft consistency compared to other lymphomas
Prominent blood vessels visible grossly
Tan discoloration in areas with clear cells
Preservation of capsule in many cases
Extension beyond capsule in advanced cases.
Size Location:
Node size typically 2-8 cm
Multiple nodal groups involved at presentation
Mediastinal involvement less common than peripheral nodes
Abdominal lymphadenopathy frequent
Retroperitoneal nodes commonly involved
Extranodal involvement at presentation uncommon
Hepatosplenomegaly common.
Multifocality:
Generalized lymphadenopathy at presentation (>90%)
Stage III-IV disease in majority of cases
Bone marrow involvement in 50-70%
Liver involvement common
Spleen involvement frequent
Skin involvement in 40-50%
CNS involvement rare but described.
Microscopic Description
Histological Features:
Partial effacement of lymph node architecture with residual follicles
Polymorphic infiltrate with clear cells, immunoblasts, and inflammatory cells
Prominent high endothelial venules and vascular proliferation
Follicular dendritic cell (FDC) meshworks expanded beyond follicles
Clear cells with pale cytoplasm are characteristic
Plasma cells and eosinophils in background.
Cellular Characteristics:
Clear cells (medium-sized with clear cytoplasm and round nuclei)
Immunoblasts (large cells with prominent nucleoli)
Small lymphocytes admixed
Plasma cells scattered throughout
Eosinophils often present
Epithelioid cells may be seen
Reed-Sternberg-like cells occasionally present
EBV-positive B-immunoblasts in many cases.
Architectural Patterns:
Partial architectural preservation with residual follicles
Interfollicular expansion by neoplastic infiltrate
Prominent vascular proliferation throughout
Expanded FDC networks extending beyond follicles
Sinusoidal infiltration may occur
Capsular involvement frequent
Perinodal extension in advanced cases.
Grading Criteria:
No formal grading system as uniformly aggressive
Degree of architectural effacement varies
Proportion of clear cells variable
Proliferation index (Ki-67) typically 30-70%
EBV-positive cells quantity varies
Pattern variants recognized but not graded
Transformation to large B-cell lymphoma may occur.
Immunohistochemistry
Positive Markers:
CD3 (positive in neoplastic T-cells)
CD4 (positive, helper phenotype)
PD1 (strongly positive, follicular helper marker)
CXCL13 (positive, follicular helper marker)
BCL6 (positive in neoplastic cells)
ICOS (follicular helper marker)
CD10 (may be positive)
SAP/SH2D1A (follicular helper marker).
Negative Markers:
CD8 (negative in typical cases)
CD20 (negative in T-cells, positive in reactive B-cells)
CD30 (negative in typical AITL)
ALK (negative)
CD56 (negative)
TIA-1 and Granzyme B (negative)
CD5 (may be lost)
CD7 (may be lost).
Diagnostic Utility:
Follicular helper markers (PD1, CXCL13) are diagnostic
CD21 and CD23 highlight expanded FDC networks
EBV (EBER) positive in B-immunoblasts
Ki-67 shows moderate to high proliferation
CD68 highlights epithelioid cells
Vascular markers (CD31, CD34) show prominent vascularity
IgG4 staining may be helpful.
Molecular Subtypes:
TFH phenotype (PD1+, CXCL13+, BCL6+)
Pattern I (hyperplastic follicles with clear cell infiltrate)
Pattern II (depleted follicles with FDC expansion)
Pattern III (total architectural effacement)
EBV-positive subset (worse prognosis)
IgG4-positive subset (uncertain significance).
Molecular/Genetic
Genetic Mutations:
TET2 mutations (80-90% of cases)
DNMT3A mutations (30-40%)
IDH2 mutations (20-30%, R172 hotspot)
RHOA mutations (50-70%, G17V hotspot)
FYN-TRAF3IP2 fusion rare
TP53 mutations in subset
CARD11 mutations
Complex chromosomal abnormalities.
Molecular Markers:
Clonal TCR gene rearrangements
Gene expression profiling shows TFH signature
Hypomethylation due to TET2 mutations
Dysregulated DNA methylation
JAK/STAT pathway alterations
PI3K/AKT pathway activation
B-cell helper function dysregulation
Cytokine dysregulation.
Prognostic Significance:
Poor prognosis overall (5-year OS 30-35%)
Age >60 years indicates worse outcome
Advanced stage at presentation common
IPI score correlates with survival
EBV positivity may indicate worse prognosis
Bone marrow involvement affects outcome
Pattern III histology associated with worse prognosis.
Therapeutic Targets:
CHOP-like chemotherapy (standard first-line)
Hypomethylating agents (5-azacytidine, decitabine)
Histone deacetylase inhibitors
Autologous stem cell transplant in selected patients
Allogeneic transplant for relapsed disease
Targeted therapy under investigation
Immunomodulatory agents.
Differential Diagnosis
Similar Entities:
Reactive follicular hyperplasia with prominent clear cells
Progressive transformation of germinal centers
Hyaline-vascular Castleman disease
Infectious mononucleosis (EBV-related)
Other T-cell lymphomas (PTCL-NOS, ALCL)
Classical Hodgkin lymphoma
Autoimmune lymphadenopathy.
Distinguishing Features:
AITL: TFH markers+, clear cells, expanded FDC networks, clonal TCR
Reactive hyperplasia: polyclonal, preserved architecture
PTGL: progressive transformation pattern, polyclonal
Castleman disease: specific morphology, no clonality
PTCL-NOS: lacks TFH markers
Hodgkin lymphoma: Reed-Sternberg cells, CD15+, CD30+.
Diagnostic Challenges:
Reactive vs neoplastic distinction challenging
Partial architectural preservation may suggest reactive process
Polymorphic infiltrate can be confusing
EBV-positive B-cells may dominate
Limited tissue may prevent full evaluation
Need for comprehensive immunophenotype
Molecular studies often required.
Rare Variants:
AITL with increased large cells
AITL with prominent epithelioid cells
AITL with amyloid deposition
AITL with transformation to DLBCL
Composite lymphomas (rare)
Cutaneous involvement patterns
CNS involvement (rare).
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 biopsy from [anatomical site], measuring [size] cm
Primary Diagnosis
Angioimmunoblastic T-cell lymphoma (AITL)
WHO Classification
Angioimmunoblastic T-cell lymphoma (WHO 2016)
Histological Features
Shows partial architectural effacement with clear cells, prominent vascularity, and expanded follicular dendritic cell networks
Cellular Composition
Polymorphic infiltrate with clear cells, immunoblasts, small lymphocytes, plasma cells, and eosinophils
Architectural Pattern
Pattern: [I/II/III]; FDC networks: expanded; Vascular proliferation: prominent
Immunohistochemistry
T-cells: CD3+, CD4+, PD1+, CXCL13+, BCL6+; FDC: CD21+, CD23+; Ki-67: [percentage]%
EBV Studies
EBER: [positive/negative] in B-immunoblasts; EBV-positive cells: [few/many/numerous]
Molecular Studies
T-cell receptor rearrangement: clonal; [Additional molecular findings if available]
Staging Information
Clinical stage: [I/II/III/IV]; Bone marrow involvement: [present/absent]; B-symptoms: [present/absent]
Final Diagnosis
Angioimmunoblastic T-cell lymphoma, WHO 2016