Definition/General
Introduction:
T-cell lymphomas represent a heterogeneous group of malignant neoplasms derived from T-lymphocytes at various stages of differentiation
They constitute 10-15% of all non-Hodgkin lymphomas in Western countries but show higher incidence in Asia
These lymphomas are characterized by aggressive clinical behavior in most subtypes
They show diverse morphological features and complex immunophenotypes
Molecular characterization is increasingly important for classification.
Origin:
Originates from T-lymphocytes at different stages of maturation
Precursor T-cell neoplasms arise from immature T-cells
Mature T-cell neoplasms arise from post-thymic T-cells
NK-cell lineage neoplasms are closely related
Shows clonal T-cell receptor gene rearrangements
Oncogenic mutations drive neoplastic transformation
Viral infections play role in some subtypes (HTLV-1, EBV).
Classification:
WHO classification divides into precursor and mature T/NK-cell neoplasms
Precursor T-lymphoblastic lymphoma/leukemia
Mature T-cell lymphomas include multiple subtypes
Peripheral T-cell lymphoma, NOS (most common)
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma
Cutaneous T-cell lymphomas
NK/T-cell lymphomas
Site-specific variants recognized.
Epidemiology:
Geographic variation in incidence (higher in Asia)
Peak incidence in 5th-6th decades for most types
Male predominance in most subtypes
Environmental factors may contribute
Viral associations vary by region
Indian subcontinent shows higher incidence of certain subtypes
Prognosis generally worse than B-cell lymphomas.
Clinical Features
Presentation:
Lymphadenopathy (peripheral and deep nodes)
Extranodal involvement common (60-80%)
B-symptoms frequent (fever, night sweats, weight loss)
Hepatosplenomegaly in many cases
Skin involvement in cutaneous types
GI involvement in enteropathy-associated types
Bone marrow involvement variable
CNS involvement in aggressive subtypes.
Symptoms:
Constitutional symptoms common (60-80%)
Fever of unknown origin
Significant weight loss (>10% body weight)
Drenching night sweats
Fatigue and weakness
Pruritus in some cases
Organ-specific symptoms depending on site
Performance status often compromised
Hemophagocytic syndrome may develop.
Risk Factors:
Age (peak in 5th-6th decades)
Male gender for most subtypes
Immunodeficiency states (HIV, transplant)
Autoimmune diseases (celiac disease for EATL)
Viral infections (HTLV-1, EBV, HTLV-2)
Chemical exposure (pesticides, solvents)
Previous chemotherapy or radiation
Geographic factors (endemic areas).
Screening:
No routine screening available
High index of suspicion for high-risk populations
Complete blood count and peripheral smear
Comprehensive metabolic panel
LDH and β2-microglobulin
Imaging studies for staging
Viral serologies (HTLV-1, EBV, hepatitis)
Bone marrow biopsy for staging.
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Gross Description
Appearance:
Enlarged lymph nodes with loss of normal architecture
Firm to hard consistency
Gray-white cut surface with fish-flesh appearance
Necrosis and hemorrhage may be present
Matted lymph nodes in advanced cases
Extranodal masses show infiltrative growth
Skin lesions range from patches to tumors.
Characteristics:
Fish-flesh appearance typical of lymphomas
Homogeneous gray-white cut surface
Firm consistency due to cellular infiltrate
Capsular involvement and extension common
Necrosis more common than in B-cell lymphomas
Hemorrhage may be prominent
Fibrosis variable depending on subtype.
Size Location:
Node size typically 2-10 cm
Multiple nodal groups involved
Extranodal sites commonly affected
GI tract involvement in EATL
Skin involvement in cutaneous types
Liver and spleen frequently involved
Bone marrow involvement variable
CNS involvement in aggressive types.
Multifocality:
Multifocal involvement common at presentation
Disseminated disease frequent
Extranodal spread characteristic
Systemic involvement in most cases
Contiguous spread less predictable than Hodgkin lymphoma
Hematogenous dissemination early in course
Sanctuary sites (CNS, testes) may be involved.
Microscopic Description
Histological Features:
Polymorphic cell population in many subtypes
Medium to large cells predominantly
Irregular nuclear contours common
Prominent nucleoli in many cases
Abundant mitotic activity
Background inflammatory cells (eosinophils, histiocytes, plasma cells)
Vessel proliferation in some subtypes
Necrosis may be extensive.
Cellular Characteristics:
Pleomorphic T-cells with irregular nuclei
Medium to large cell size
Vesicular chromatin
Prominent nucleoli
Moderate to abundant cytoplasm
High nuclear-cytoplasmic ratio
Frequent mitoses and apoptotic figures
Anaplastic features in some subtypes
Reed-Sternberg-like cells may be present.
Architectural Patterns:
Diffuse growth pattern most common
Paracortical expansion in lymph nodes
Sinusoidal infiltration may occur
Perivascular distribution characteristic of some types
Epitheliotropism in cutaneous types
Angioinvasion in NK/T-cell types
Nodular pattern rare
Follicular pattern exceptional.
Grading Criteria:
No formal grading system for most T-cell lymphomas
Proliferation index (Ki-67) important prognostic factor
Large cell morphology generally indicates aggressive behavior
Degree of pleomorphism noted
Mitotic rate assessment
Necrosis extent may impact prognosis
Transformation from indolent to aggressive types possible.
Immunohistochemistry
Positive Markers:
CD3 (pan-T-cell marker, positive in most)
CD2 (T-cell marker)
CD5 (positive in many subtypes)
CD7 (often lost in neoplastic T-cells)
CD4 or CD8 (helper vs cytotoxic phenotype)
TCR-αβ or TCR-γδ
Granzyme B (cytotoxic markers)
Perforin (cytotoxic marker)
TIA-1 (cytotoxic marker).
Negative Markers:
CD20 (B-cell marker, negative)
PAX5 (B-cell marker, negative)
CD79a (B-cell marker, negative)
CD10 (usually negative)
BCL6 (usually negative)
CD23 (negative)
Cyclin D1 (negative)
CD138 (negative except plasma cell differentiation).
Diagnostic Utility:
T-cell lineage confirmation with CD3
Subset identification with CD4/CD8
Activation markers (CD30, CD25) in some subtypes
Cytotoxic phenotype assessment
Loss of pan-T-cell antigens supports neoplasia
TCR expression helps define lineage
Ki-67 assesses proliferation
Specific markers for subtypes (ALK, EBER, etc.).
Molecular Subtypes:
TCR-αβ positive (majority of cases)
TCR-γδ positive (subset with different behavior)
CD4-positive helper phenotype
CD8-positive cytotoxic phenotype
Double-negative (CD4-, CD8-) subset
Double-positive (rare in mature T-cells)
NK-cell phenotype (CD3-, CD56+)
Cytotoxic markers expression pattern.
Molecular/Genetic
Genetic Mutations:
T-cell receptor gene rearrangements (clonal)
TP53 mutations common in aggressive types
RHOA mutations in angioimmunoblastic T-cell lymphoma
TET2 mutations in AITL
DNMT3A mutations
IDH2 mutations in AITL
FYN-TRAF3IP2 fusion in some cases
NPM-ALK translocation in ALK+ ALCL.
Molecular Markers:
Clonal TCR gene rearrangements
Chromosomal translocations in specific subtypes
Gene expression profiling increasingly used
Tumor suppressor gene inactivation
Oncogene activation
Epigenetic modifications
MicroRNA dysregulation
Copy number alterations.
Prognostic Significance:
Generally poor prognosis compared to B-cell lymphomas
5-year overall survival 30-40% for most types
ALK-positive ALCL has better prognosis
Cutaneous T-cell lymphomas variable prognosis
Advanced stage at presentation common
High IPI scores frequent
Transformation to aggressive types worsens outcome.
Therapeutic Targets:
Standard chemotherapy (CHOP-like regimens)
CD30-directed therapy (brentuximab vedotin)
ALK inhibitors for ALK+ cases
Histone deacetylase inhibitors
Proteasome inhibitors
Immunomodulatory agents
Checkpoint inhibitors (PD-1/PD-L1)
CAR-T cell therapy under investigation.
Differential Diagnosis
Similar Entities:
B-cell lymphomas (immunohistochemistry distinguishes)
Classical Hodgkin lymphoma (Reed-Sternberg cells, different immunoprofile)
Reactive T-cell hyperplasia (polyclonal, preserved architecture)
Infectious processes (EBV, CMV, etc.)
Autoimmune lymphadenopathy
Metastatic carcinoma (cytokeratin positive)
Langerhans cell histiocytosis.
Distinguishing Features:
T-cell lymphomas: CD3+, CD20-, clonal TCR
B-cell lymphomas: CD20+, CD3-, clonal IGH
Hodgkin lymphoma: CD15+, CD30+, background inflammatory cells
Reactive hyperplasia: polyclonal, preserved architecture
Infections: specific organisms, usually polyclonal
Carcinoma: cytokeratin+, CD45-
Molecular studies help confirm clonality.
Diagnostic Challenges:
Heterogeneous morphology creates diagnostic difficulty
Loss of T-cell antigens may obscure lineage
Mixed inflammatory background can mask neoplastic cells
Reactive vs neoplastic distinction challenging
Subtype classification requires expertise
Limited tissue samples
Need for multiple immunostains
Molecular confirmation often required.
Rare Variants:
Composite lymphomas (T-cell and B-cell components)
Histiocyte-rich variants
Sclerotic variants with prominent fibrosis
Anaplastic variants mimicking carcinoma
Small cell variants
Blastoid variants
Pleomorphic variants
Transformation from indolent to aggressive types.
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
[Biopsy type] from [anatomical site], measuring [size] cm
Primary Diagnosis
T-cell lymphoma, [specific subtype if determinable]
WHO Classification
[Specific T-cell lymphoma subtype] (WHO 2016 classification)
Histological Features
Shows [architectural pattern] with [cell size] pleomorphic T-cells and [background inflammatory cells]
Cellular Morphology
Neoplastic cells are [size] with [nuclear features] and [mitotic activity]
Immunohistochemistry
CD3+, [CD4+/CD8+ or CD4-/CD8-], [other T-cell markers], CD20-, Ki-67: [percentage]%
Molecular Studies
T-cell receptor gene rearrangement: [clonal/polyclonal]; [Additional molecular findings]
Staging Information
Clinical stage: [I/II/III/IV]; Extranodal involvement: [present/absent]
Prognostic Factors
IPI score: [low/intermediate/high]; Ki-67: [percentage]%; [Other relevant factors]
Final Diagnosis
[Specific T-cell lymphoma subtype], WHO 2016