What is the link between T‑cell lymphoma and hemolytic disorders in a patient presenting with anemia?

Link Between T-Cell Lymphoma and Hemolytic Disorders

T-cell lymphomas are strongly associated with hemolytic disorders, primarily through two distinct mechanisms: direct malignancy-triggered hemophagocytic lymphohistiocytosis (HLH) and autoimmune hemolytic anemia (AIHA), with T-cell and NK-cell lymphomas accounting for 35% of all malignancy-associated HLH cases. 1

Primary Mechanisms of Association

Hemophagocytic Lymphohistiocytosis (HLH)

T-cell and NK-cell lymphomas are the most frequent hematologic triggers of malignancy-associated HLH, particularly in Asian populations. 1

• Specific T-cell subtypes with highest HLH risk include:

  • Peripheral T-cell lymphomas, especially subcutaneous panniculitis-like T-cell lymphoma 1
  • Primary cutaneous γδ-T-cell lymphoma 1
  • Anaplastic large cell lymphomas (less commonly) 1

• Pathophysiology involves cytokine-mediated hyperinflammation: Malignant T-cells secrete interferon-γ and interleukin-6, driving systemic inflammatory responses that result in hemolysis, cytopenias, and hemophagocytosis 1

• Geographic variation exists: While T-cell neoplasms predominate as HLH triggers in Japan, China, and Korea (accounting for the majority of cases), they remain a significant cause in Western countries where they represent 35% of malignancy-triggered HLH 1

Autoimmune Hemolytic Anemia (AIHA)

T-cell lymphomas can directly cause AIHA through immune dysregulation, though this association is less well-characterized than in B-cell malignancies. 2, 3, 4

• Angioimmunoblastic T-cell lymphoma (AITL) has particular propensity for autoimmune phenomena: AITL characteristically presents with constitutional symptoms and autoimmune-related findings including hemolytic anemia, due to its inherent immune dysregulation 2

• Warm antibody-mediated hemolysis predominates: Case reports document IgG-mediated warm AIHA in immunoblastic lymphadenopathy-like T-cell lymphoma and enteropathy-associated T-cell lymphoma (EATL) type II 3, 4

• T-cell large granular lymphocyte (T-LGL) leukemia represents a distinct entity: CD3+ T-LGL leukemia frequently associates with autoimmune hemolytic anemia, neutropenia, and thrombocytopenia, with splenectomy showing efficacy in resolving hemolysis despite persistence of the malignant clone 5

Clinical Recognition and Diagnostic Approach

When to Suspect the Association

• In adults with HLH, nearly half have underlying malignancy, with likelihood increasing with age 1

• Key clinical features suggesting T-cell lymphoma-associated hemolysis include:

  • Generalized lymphadenopathy with constitutional symptoms (fever, weight loss, night sweats) 2, 3
  • Positive direct antiglobulin test (Coombs test) with evidence of hemolysis (elevated indirect bilirubin, low haptoglobin, elevated LDH, reticulocytosis) 3, 4
  • Cytopenias affecting multiple cell lines 4, 5
  • Splenomegaly and hepatomegaly 2

Essential Diagnostic Workup

• Lymph node biopsy by experienced hematopathologist with comprehensive immunophenotyping: Include CD3, CD4, CD8, CD30, CD56, TCRαβ, TCRγδ, and T-follicular helper markers (PD1, CXCL13, ICOS) 1

• Molecular analysis for clonal T-cell receptor gene rearrangements 1, 3, 4

• For suspected HLH, assess: Fever, splenomegaly, cytopenias, ferritin (rapidly increases in active HLH), fibrinogen, soluble CD25, triglycerides, and bone marrow examination for hemophagocytosis 1

• Direct antiglobulin test and hemolysis markers: Haptoglobin, indirect bilirubin, LDH, reticulocyte count 3, 4

Management Implications

Treatment Strategy Depends on Mechanism

For Malignancy-Triggered HLH:

• Treating the underlying T-cell lymphoma is paramount 1
• Concurrent HLH-directed therapy may be necessary for life-threatening hyperinflammation 1
• Differentiate from infection-triggered HLH during chemotherapy, as both may coexist 1

For AIHA Associated with T-Cell Lymphoma:

• Corticosteroids remain first-line for warm antibody AIHA 3, 4
• However, AIHA may be refractory to steroids alone, necessitating lymphoma-directed therapy 3, 4
• In T-LGL leukemia with AIHA, splenectomy can provide durable resolution of hemolysis despite persistent lymphocytosis 5

Critical Pitfalls to Avoid

• Do not dismiss hemolysis as solely autoimmune without evaluating for underlying lymphoma: The temporal relationship between lymphoma diagnosis and hemolysis varies—AIHA may precede, occur concurrently with, or follow lymphoma diagnosis 6, 3

• Do not attribute all cytopenias to bone marrow infiltration: Immune-mediated cytopenias actually carry better prognosis than marrow infiltration-related cytopenias 1

• Recognize that infection may coexist with malignancy-triggered HLH: The presence of infection does not exclude malignancy as the primary HLH trigger 1

• In patients with known T-cell lymphoma developing new hemolysis, consider both disease progression and treatment-related immunosuppression with secondary infection 1