What are the diagnostic and treatment approaches for T-cell lymphoma?

T-Cell Lymphoma: Diagnostic and Treatment Approach

Diagnostic Workup

The diagnosis of T-cell lymphoma requires an excisional lymph node biopsy with comprehensive histopathological, immunophenotypic, and molecular analysis—fine needle aspirations and core biopsies are inadequate and should only be used in rare emergency situations. 1

Essential Tissue Analysis

• Histology must include: Pan-T-cell markers (CD3, CD5, CD2, CD7), subset markers (CD4, CD8, CD30, CD56), B-cell markers (CD20), proliferation markers (Ki-67), and specialized markers based on suspected subtype (ALK, TCRbeta, TCRdelta, PD1/CD279, CXCL13, ICOS for follicular helper phenotype) 1
• Molecular studies: TCR gene rearrangement analysis to detect clonal T-cell populations, ALK translocation detection [t(2;5) or variants], DUSP22 and TP63 rearrangements for ALCL ALK-negative cases 1
• EBV evaluation: EBER in situ hybridization is mandatory, as EBV positivity occurs in specific subtypes (NK/T-cell lymphomas, some PTCL-NOS) and affects prognosis and treatment selection 1

Staging Evaluation

All patients require PET/CT of chest, abdomen, and pelvis, bone marrow biopsy with aspirate, complete blood count with differential, comprehensive metabolic panel including LDH, and full skin examination. 1

• Additional imaging: CT or MRI of head/neck may be useful in selected cases, particularly for NK/T-cell lymphomas where PET/CT is essential for staging and treatment planning 1
• Cardiac assessment: Multigated acquisition scan or echocardiogram is required before anthracycline-based chemotherapy 1
• Serology testing: HIV, HTLV-1, hepatitis B and C screening—HTLV-1 positivity changes the diagnosis to adult T-cell leukemia/lymphoma with different management 1

Critical Diagnostic Pitfalls

• For cutaneous presentations: Multiple skin biopsies from indurated areas are often required, with ellipse biopsies preferred over punch biopsies 1
• For mycosis fungoides/Sézary syndrome: Flow cytometry of peripheral blood (CD4+/CD7- or CD4+/CD26-) and Sézary cell count are essential, though debatable in early-stage MF without SS suspicion 1
• Bone marrow examination: Required for all PTCL variants except lymphomatoid papulosis and early-stage MF (stage IA/IB), but essential for subcutaneous panniculitis-like T-cell lymphoma and primary cutaneous gamma/delta T-cell lymphoma 1

Risk Stratification

The International Prognostic Index (IPI) remains the standard prognostic tool for nodal PTCL, with male sex representing an additional adverse prognostic factor. 1

• For NK/T-cell lymphomas: High EBV-DNA copy number correlates with tumor load and predicts adverse outcomes 1
• For ALCL ALK-negative: DUSP22 rearrangement confers favorable prognosis similar to ALK-positive disease 1

Treatment Approach

Nodal PTCL (PTCL-NOS, AITL, ALCL)

For patients under 60-65 years with good performance status, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) followed by autologous stem cell transplantation in chemosensitive patients represents the evidence-based standard approach. 1, 2

• CHOEP regimen specifics: 6 courses of bi-weekly CHOEP achieves 82% overall response rate with 51% complete response, with 5-year overall survival of 70% for ALCL ALK-, 52% for AITL, and 47% for PTCL-NOS 1
• For ALCL ALK-positive with low-risk IPI: Consolidation with autologous transplant is not required, as outcomes are favorable with chemotherapy alone 1
• Alternative for older patients (>60-65 years): Standard CHOP without etoposide, as CHOEP toxicity is limiting in this population 1

NK/T-Cell Lymphomas

Anthracycline-based regimens are ineffective due to multidrug resistance phenotype—L-asparaginase-containing regimens (SMILE or AspaMetDex) are mandatory. 2, 3

• Stage I/II nasal disease: Asparaginase-based chemotherapy plus sequential or concurrent radiotherapy 3
• Stage III/IV or non-nasal disease: Asparaginase-containing regimens consolidated by allogeneic (not autologous) hematopoietic stem cell transplantation in suitable patients 3
• Monitoring: Serial plasma EBV DNA and PET/CT to achieve undetectable EBV DNA and Deauville score ≤3 3

Cutaneous T-Cell Lymphomas (Mycosis Fungoides/Sézary Syndrome)

Early-stage disease (IA/IB) requires skin-directed therapies only, as disease-specific and overall survival are favorable without systemic treatment. 1, 4

• Advanced-stage disease: Escalating systemic therapies including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies 4
• Allogeneic stem cell transplantation: Reserved for highly-selected patients, as this may be curative in some cases 4

Response Evaluation and Surveillance

Radiological assessment should occur after every 2-4 cycles of therapy, at treatment completion, and whenever response is questioned. 1

• Clinical monitoring: History and physical examination every 3-6 months for 2 years, then as clinically indicated 1
• Surveillance imaging: No more often than every 6 months for 2 years, then annually for 5 years or as clinically indicated 1
• Laboratory monitoring: Complete blood count, comprehensive metabolic panel, and LDH at baseline and during follow-up 1

Treatment Modification Triggers

• Incomplete or lacking response: Early evaluation for salvage regimens is required 5
• PET/CT findings: Residual FDG-avid lesions lack specificity and require biopsy confirmation before changing management 1

Critical Treatment Pitfalls to Avoid

• Never use anthracycline-based regimens for NK/T-cell lymphomas—they are uniformly ineffective due to multidrug resistance 2, 3
• Never administer G-CSF during concurrent chest radiotherapy—this causes severe complications; G-CSF should only be given 24-72 hours after chemotherapy completion 6
• Avoid autologous stem cell transplantation for NK/T-cell lymphomas—it does not improve outcomes; allogeneic transplant is required 3
• Do not use extended-field radiotherapy techniques—involved-field approaches provide equivalent outcomes with reduced toxicity 6