Explain proliferative T‑cell lymphoma, including typical adult age range, male predominance, clinical presentation, diagnostic criteria, treatment options, and prognosis.

Peripheral T-Cell Lymphomas: Overview

Peripheral T-cell lymphomas (PTCLs) are uncommon, heterogeneous malignant lymphoproliferative disorders originating from post-thymic (peripheral) T cells or mature natural killer (NK) cells, representing 10-15% of all non-Hodgkin's lymphomas with generally poor prognosis. 1

Epidemiology and Age Distribution

• PTCLs predominantly affect adults with a median age at diagnosis in the 60s, though specific age ranges vary by subtype 1
• Male predominance is documented as an adverse prognostic factor across PTCL subtypes 1
• Geographic variation exists: nodal subtypes predominate in Caucasian patients (>80% in Europe), while extranodal NK/T-cell lymphoma is endemic in Asia due to Epstein-Barr virus association 1

Major PTCL Subtypes

Nodal PTCLs (Most Common in Western Populations)

PTCL-Not Otherwise Specified (PTCL-NOS):

• Represents 34% of PTCLs in Europe 1
• Immunophenotype: CD4>CD8, frequent antigen loss (CD5, CD7), CD30+/−, CD56+/− 1
• Presumed cell of origin: variable, mostly T-helper cell 1

Angioimmunoblastic T-Cell Lymphoma (AITL):

• Comprises 28% of European PTCLs 1
• Characteristic features: CD4+, CD10+/−, CXCL13+, hyperplasia of follicular dendritic cells, EBV+ B blasts 1
• Originates from follicular T-helper cells 1

Anaplastic Large-Cell Lymphoma (ALCL):

• ALK-positive: 6% of PTCLs, better prognosis 1
• ALK-negative: 9% of PTCLs 1
• Both express CD30+, EMA+, CD25+, cytotoxic granules 1
• Originate from cytotoxic T-cells 1

Extranodal PTCLs

Enteropathy-Associated T-Cell Lymphoma (EATL):

• More frequent in Northern Europe (9-10%) due to HLA haplotypes associated with coeliac disease 1
• Type 1: CD8+/−, CD56−, associated with pre-existing enteropathy 1
• Type 2: CD8+, CD56+, no pre-existing enteropathy 1

Extranodal NK/T-Cell Lymphoma (ENKTCL):

• Represents 44% of PTCLs in Asia (excluding Japan) 1
• Strongly EBV-associated 1
• Immunophenotype: CD2+, CD56+, surface CD3−, cytoplasmic CD3ε+, granzyme B+, EBV+ 1

Hepatosplenic T-Cell Lymphoma (HSTCL):

• Associated with Crohn's disease 1
• Immunophenotype: CD3+, CD56+/−, CD4−, CD8+/−, CD5−, TIA1+ 1
• Predominantly γδ T-cell receptor 1

Clinical Presentation

Common presenting features across PTCL subtypes include:

• Lymphadenopathy (nodal subtypes) 1
• B symptoms (fever, night sweats, weight loss) 1
• Elevated lactate dehydrogenase (LDH) 1
• Extranodal involvement varies by subtype 1

Subtype-specific presentations:

• AITL: generalized lymphadenopathy, hepatosplenomegaly, skin rash, autoimmune phenomena 1
• ENKTCL: nasal/paranasal destruction, facial swelling 1
• EATL: abdominal pain, intestinal perforation, malabsorption 1
• HSTCL: hepatosplenomegaly without lymphadenopathy 1

Diagnostic Criteria

Diagnosis must be made by an expert haematopathologist using excisional tumor tissue biopsy providing adequate material for formalin-fixed samples. 1

Essential diagnostic components per WHO classification:

• Integration of clinical picture, morphology, immunohistochemistry, flow cytometry, cytogenetics, and molecular biology 1
• Demonstration of neoplastic T-cell population based on: (i) morphology, (ii) aberrant T-cell phenotype, (iii) clonally rearranged T-cell receptor genes (αβ versus γδ genotypes) 1

Required staging workup:

• Complete blood count and routine blood chemistry including LDH and uric acid 1
• Screening for HIV, HTLV-1, hepatitis B and C 1
• CT scan of chest and abdomen 1
• Bone marrow aspirate and biopsy 1
• 18F-FDG PET/CT increasingly used for baseline and re-staging, particularly valuable in ENKTCL 1

Special diagnostic considerations:

• CD30 expression is central for ALCL recognition 1
• ALK status (positive vs negative) determined by t(2;5) translocation or variants 1
• EBV assessment (EBER in situ hybridization) important as some entities show EBER positivity in neoplastic cells 1
• High EBV-DNA copy number in ENKTCL correlates with tumor load and adverse outcome 1

Prognostic Assessment

The International Prognostic Index (IPI) remains the recommended prognostic tool for nodal PTCLs in clinical practice. 1

Adverse prognostic factors:

• Male sex 1
• High IPI score 1
• Elevated LDH 1
• High EBV-DNA copy number in ENKTCL 1

Treatment Options

First-Line Therapy for Nodal PTCLs

Treatment strategies must be adapted according to age, IPI score, and comorbidities; inclusion in clinical trials is strongly recommended whenever possible. 1

Standard chemotherapy approaches:

• CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) or variants remain most commonly used 1
• CHOEP (CHOP plus etoposide) shows outcome benefits in event-free survival for patients <60 years with ALCL ALK+ histology, though toxicity limits use in older patients 1
• Six courses of bi-weekly CHOEP followed by autologous stem-cell transplantation demonstrated favorable responses in treatment-naïve PTCL patients 1

Consolidation Strategies

Autologous stem-cell transplantation (autoSCT) in first remission is recommended for eligible younger patients to achieve higher response and survival rates. 1

Relapsed/Refractory Disease

Targeted approaches for relapsed disease include:

• Ibrutinib 1
• Lenalidomide 1
• Temsirolimus 1
• Bortezomib (preferable in combination with chemotherapy) 1
• Alternatively, repeat previous therapy if long remissions were achieved 1

Allogeneic stem cell transplantation should be considered for eligible patients with relapsed/refractory disease. 2

Prognosis

PTCLs generally carry poor prognosis compared to B-cell lymphomas, with significant variation by subtype:

ALCL ALK-positive:

• Best prognosis among PTCLs 1
• Benefits from CHOEP regimen in younger patients 1

ALCL ALK-negative:

• Intermediate prognosis 1

PTCL-NOS and AITL:

• Generally aggressive with poor outcomes 1
• Median overall survival varies but typically measured in months to few years without intensive therapy 2

ENKTCL:

• Aggressive course 1
• Prognosis influenced by EBV-DNA levels 1

HSTCL:

• Extremely aggressive with very poor prognosis 1

Survival outcomes with intensive therapy:

• Overall response rate to induction: 50% in aggressive subtypes 2
• Complete remission rate: 10% with standard therapy 2
• Median overall survival: 51 months for entire group, 84 months for patients undergoing allogeneic stem cell transplantation versus 34 months for non-transplant patients 2

Critical Pitfalls to Avoid

• Do not rely on fine needle aspiration; excisional biopsy is mandatory for accurate diagnosis and subtype classification 1
• Do not assume all PTCLs behave similarly; subtype-specific treatment approaches are essential 1
• Do not omit HTLV-1 screening, particularly in endemic regions or patients from endemic areas, as adult T-cell leukemia/lymphoma requires distinct management 1, 3
• Do not delay referral for stem cell transplantation evaluation in eligible patients, as this represents the best chance for long-term survival 2
• Residual FDG-avid lesions on PET lack specificity; biopsy confirmation is recommended 1