Definition/General
Introduction:
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) represents a heterogeneous group of mature T-cell lymphomas that do not fit into any of the specifically defined T-cell lymphoma categories
It constitutes 25-30% of all T-cell lymphomas
These lymphomas are characterized by aggressive clinical behavior and poor prognosis
The diagnosis is made by exclusion after ruling out other specific T-cell lymphoma subtypes.
Origin:
Originates from post-thymic mature T-cells at various stages of activation and differentiation
Shows clonal T-cell receptor gene rearrangements
Helper T-cell phenotype (CD4+) more common than cytotoxic (CD8+)
May arise from follicular helper T-cells in some cases
Shows evidence of activation with expression of activation markers
Oncogenic mutations drive malignant transformation.
Classification:
WHO classification defines as diagnosis of exclusion
Must exclude anaplastic large cell lymphoma
Must exclude angioimmunoblastic T-cell lymphoma
Must exclude adult T-cell leukemia/lymphoma
Must exclude extranodal NK/T-cell lymphoma
Must exclude other specific subtypes
Nodal and extranodal presentations recognized
Grade not applicable but generally high-grade.
Epidemiology:
Peak incidence in 6th decade of life
Male predominance (M:F = 1.5-2:1)
Higher incidence in East Asia compared to Western countries
Most common T-cell lymphoma in adults
Represents 6-10% of all non-Hodgkin lymphomas
Indian population shows higher frequency than Western populations
Poor prognosis compared to B-cell lymphomas.
Clinical Features
Presentation:
Lymphadenopathy (generalized or localized)
Extranodal involvement common (>65%)
B-symptoms frequent (>50%)
Advanced stage at presentation (75% Stage III-IV)
Bone marrow involvement (20-25%)
Hepatosplenomegaly common
Skin involvement (15-20%)
GI tract involvement may occur.
Symptoms:
Constitutional symptoms prominent
Fever (most common B-symptom)
Night sweats
Significant weight loss (>10% body weight)
Fatigue and weakness
Pruritus occasionally
Performance status often compromised
Hemophagocytic syndrome may develop (5-10%)
Tumor lysis syndrome possible.
Risk Factors:
Age (peak 6th decade)
Male gender
Geographic factors (higher in Asia)
Immunodeficiency states (HIV, transplant recipients)
Autoimmune diseases (rheumatoid arthritis, Sjögren syndrome)
Previous malignancy rare association
Viral infections (EBV in some cases)
Environmental exposures (pesticides, chemicals).
Screening:
No routine screening available
Complete blood count may show cytopenias
Peripheral blood smear for circulating tumor cells
Comprehensive metabolic panel
LDH elevation common (>75%)
β2-microglobulin elevation
Imaging studies for staging (CT, PET-CT)
Bone marrow biopsy for staging.
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Gross Description
Appearance:
Enlarged lymph nodes with effaced architecture
Firm to hard consistency
Gray-white cut surface with fish-flesh appearance
Necrosis often present
Hemorrhage may be seen
Capsular extension common
Matting of adjacent structures may occur.
Characteristics:
Fish-flesh appearance typical of high-grade lymphomas
Homogeneous gray-white to tan color
Firm consistency due to dense cellular infiltrate
Areas of necrosis common
Loss of normal architecture
Infiltrative growth pattern
Vascular congestion may be present.
Size Location:
Node size variable (2-15 cm)
Multiple nodal groups involved
Cervical and axillary nodes commonly affected
Mediastinal involvement less common
Abdominal lymphadenopathy frequent
Extranodal masses variable size
Skin lesions range from patches to tumors.
Multifocality:
Multifocal involvement at presentation common
Disseminated disease frequent (75% Stage III-IV)
Extranodal spread characteristic
Bone marrow involvement in 20-25%
Liver involvement common
Splenic involvement frequent
Multiple organ involvement indicates advanced disease.
Microscopic Description
Histological Features:
Polymorphic cell population characteristic
Medium to large pleomorphic cells
Irregular nuclear contours
Prominent nucleoli
Abundant mitotic activity
Mixed inflammatory background (eosinophils, plasma cells, histiocytes)
High-endothelial venules proliferation
Areas of necrosis common.
Cellular Characteristics:
Pleomorphic T-cells of medium to large size
Irregular, angulated nuclei
Vesicular to hyperchromatic chromatin
Prominent nucleoli (1-3 per cell)
Moderate to abundant cytoplasm
High nuclear-cytoplasmic ratio
Frequent mitotic figures
Apoptotic figures present
Reed-Sternberg-like cells occasionally seen.
Architectural Patterns:
Diffuse growth pattern most common
Paracortical expansion in lymph nodes
Interfollicular infiltration
Sinusoidal involvement may occur
Partial nodal effacement early in disease
Complete architectural effacement in advanced cases
Perivascular distribution may be prominent
Epitheliotropism rare.
Grading Criteria:
No formal grading system as generally high-grade
Proliferation index (Ki-67) typically high (>70%)
Degree of cellular pleomorphism noted
Mitotic rate invariably high
Presence of large cells indicates aggressive behavior
Necrosis extent may correlate with aggressiveness
Transformation concept not applicable.
Immunohistochemistry
Positive Markers:
CD3 (positive but may be weak or focal)
CD2 (usually positive)
CD4 (positive in 60-70% - helper phenotype)
CD8 (positive in 20-30% - cytotoxic phenotype)
CD5 (often lost in neoplastic cells)
CD7 (frequently lost)
CD25 (activation marker, often positive)
CD30 (subset positive but not uniform)
TCR-αβ (usually positive).
Negative Markers:
CD20 (B-cell marker, negative)
PAX5 (B-cell marker, negative)
CD79a (B-cell marker, negative)
CD15 (negative, helps exclude Hodgkin lymphoma)
ALK (negative, excludes ALK+ ALCL)
CD10 (usually negative)
BCL6 (negative in tumor cells)
Cyclin D1 (negative).
Diagnostic Utility:
Pan-T-cell markers establish T-cell lineage
Loss of CD5 and/or CD7 supports neoplasia
CD4/CD8 ratio helps define subset
Absence of specific markers for other T-cell lymphoma subtypes
Ki-67 shows high proliferation (>50%)
Clonality studies demonstrate monoclonal T-cell population
Exclusion of other entities crucial for diagnosis.
Molecular Subtypes:
No established molecular subtypes
Helper T-cell phenotype (CD4+) most common
Cytotoxic T-cell phenotype (CD8+) less common but more aggressive
TCR-αβ positive (majority)
TCR-γδ positive (small subset, different behavior)
Double-negative (CD4-, CD8-) rare
Follicular helper markers in subset.
Molecular/Genetic
Genetic Mutations:
Clonal TCR gene rearrangements (diagnostic requirement)
TP53 mutations common (40-50%)
TET2 mutations frequent
DNMT3A mutations
RHOA mutations (subset with follicular helper phenotype)
IDH2 mutations less common than AITL
FYN-TRAF3IP2 fusion rare
Complex karyotype common.
Molecular Markers:
Gene expression profiling shows heterogeneous patterns
Activation signatures present
Proliferation signatures prominent
Inflammatory response genes upregulated
Tumor suppressor genes frequently inactivated
Oncogenes variably activated
MicroRNA dysregulation
Epigenetic modifications common.
Prognostic Significance:
Poor prognosis overall (5-year OS 30-40%)
Worse than B-cell lymphomas of similar stage
Age important prognostic factor
Performance status critical
IPI score correlates with outcome
Extranodal sites number affects prognosis
Ki-67 >80% indicates worse outcome
TP53 mutations associated with poor prognosis.
Therapeutic Targets:
Standard chemotherapy (CHOP or CHOP-like regimens)
Autologous stem cell transplant for fit patients in first remission
CD30-directed therapy for CD30+ cases
Histone deacetylase inhibitors (romidepsin)
Checkpoint inhibitors (nivolumab, pembrolizumab)
Novel agents under investigation
Combination approaches being studied.
Differential Diagnosis
Similar Entities:
Angioimmunoblastic T-cell lymphoma (specific morphology, follicular helper markers)
Anaplastic large cell lymphoma (CD30+ uniform, hallmark cells)
Adult T-cell leukemia/lymphoma (HTLV-1+, specific morphology)
Extranodal NK/T-cell lymphoma (EBER+, angiocentric)
Classical Hodgkin lymphoma (Reed-Sternberg cells, CD15+, CD30+)
Reactive T-cell hyperplasia (polyclonal).
Distinguishing Features:
PTCL-NOS: heterogeneous morphology, lacks specific features
AITL: clear cells, follicular helper markers (PD1, CXCL13)
ALCL: uniform CD30+, hallmark cells
ATLL: HTLV-1+, flower cells
ENKTL: EBER+, angiocentric pattern
Hodgkin: CD15+, CD30+, inflammatory background
Molecular studies essential for diagnosis.
Diagnostic Challenges:
Heterogeneous morphology creates diagnostic uncertainty
Loss of T-cell antigens may obscure lineage
Mixed inflammatory background can mask neoplastic cells
Exclusion of specific subtypes requires comprehensive workup
Limited tissue may prevent full characterization
Need for multiple immunostains
Molecular confirmation often required.
Rare Variants:
T-cell/histiocyte-rich variant
Lennert lymphoma (epithelioid cell-rich)
Pleomorphic small/medium cell variant
Large cell variant
Anaplastic variant
Composite lymphomas (rare)
Transformation from other T-cell lymphomas
Primary extranodal presentations.
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
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS)
WHO Classification
Peripheral T-cell lymphoma, NOS (WHO 2016 classification)
Histological Features
Shows heterogeneous population of medium to large pleomorphic T-cells with mixed inflammatory background
Cellular Morphology
Pleomorphic T-cells with irregular nuclei, prominent nucleoli, and high mitotic activity
Exclusion of Specific Subtypes
Does not meet criteria for AITL, ALCL, ATLL, or other specific T-cell lymphoma subtypes
Immunohistochemistry
CD3+, [CD4+/CD8+], [CD5/CD7 loss pattern], CD20-, CD30 [negative/subset positive], Ki-67: [percentage]%
Molecular Studies
T-cell receptor gene rearrangement: clonal; [Additional molecular findings if available]
Staging Information
Clinical stage: [I/II/III/IV]; Extranodal involvement: [present/absent]; Bone marrow: [involved/not involved]
Prognostic Factors
IPI score: [low/intermediate/high]; Age: [years]; Performance status: [ECOG score]
Final Diagnosis
Peripheral T-cell lymphoma, not otherwise specified, WHO 2016