What are the clinical presentations, peripheral blood findings, and additional laboratory results of Acute T-Cell leukemia/lymphoma (T-Cell leukemia/lymphoma)?

Acute T-Cell Leukemia/Lymphoma (ATLL): Clinical Presentations, Peripheral Blood Findings, and Laboratory Results

Four Clinical Presentations (Shimoyama Classification)

Adult T-cell leukemia/lymphoma presents in four distinct clinical subtypes based on the Shimoyama classification, each with different prognoses and treatment implications. 1

1. Acute ATLL

• Most aggressive form with median survival <12 months 1, 2
• Lymphocytosis with elevated absolute lymphocyte count (>4,000/μL) 1

• 5% abnormal circulating T lymphocytes 1

• Hypercalcemia present (distinguishing feature from chronic/smoldering) 1
• LDH >2× normal 1
• Organomegaly, skin involvement, or lung involvement common 1
• Bone, gastrointestinal, or CNS involvement may occur 1

2. Lymphoma ATLL

• Presents with lymphomatous manifestations rather than leukemic features 1, 2
• <1% abnormal circulating cells 1
• Normal lymphocyte count 1
• Hypercalcemia present 1
• LDH >2× normal 1
• Skin or lung involvement common 1
• Aggressive clinical course similar to acute form 1, 2

3. Chronic ATLL

• Elevated lymphocyte count 1

• 5% abnormal circulating cells 1

• No hypercalcemia (key distinction from acute) 1
• LDH <2× normal 1
• Skin or lung involvement present 1
• Bone marrow or spleen involvement present 1
• Better prognosis than acute/lymphoma forms 1

4. Smoldering ATLL

• Least aggressive form 1
• Normal lymphocyte count 1

• 5% abnormal circulating cells (but low burden) 1

• No hypercalcemia 1
• LDH <1.5× normal 1
• Skin or lung involvement may be present 1
• Can progress to acute form without treatment 1

Peripheral Blood Findings

Morphologic Features

The hallmark peripheral blood finding is the presence of "flower cells"—atypical lymphocytes with markedly polylobated nuclei resembling flower petals. 1

• Flower cells characterized by: 1
  • Markedly polylobated nuclei with condensed chromatin
  • Small or absent nucleoli
  • Agranular, basophilic cytoplasm
  • Multiple morphologic variations possible
• Lymphocytosis in acute and chronic subtypes (absolute lymphocyte count >4,000/μL) 1
• ≥5% abnormal T lymphocytes required for diagnosis in leukemic forms 1
• Minimal or absent circulating abnormal cells (<1%) in lymphoma subtype 1

Immunophenotype by Flow Cytometry

Flow cytometry reveals a mature T-cell phenotype that is characteristically CD4+, CD25+, with loss of CD7 and CD26. 1

Minimum essential panel: CD3, CD4, CD7, CD8, CD25 1

Typical immunophenotype: 1

• CD4-positive (most common)
• CD25-positive (IL-2 receptor alpha; highly characteristic)
• CD2-positive
• CD5-positive
• CD45RO-positive
• CD29-positive
• TCR-αβ-positive
• HLA-DR-positive
• CD7-negative (loss is typical)
• CD26-negative (loss is typical)
• Low CD3 expression

Variant phenotypes (rare): 1

• CD8-positive
• CD4/CD8-double positive
• CD4/CD8-double negative

Additional Laboratory Results

Mandatory Diagnostic Tests

HTLV-1 seropositivity is absolutely mandatory for ATLL diagnosis and distinguishes it from other peripheral T-cell lymphomas. 1

• HTLV-1 serology (ELISA and Western blot): Must be positive 1
• Clonal integration of HTLV-1 provirus: 1
  • Should be performed in most cases
  • Mandatory in atypical presentations
  • Detected by Southern blot or inverted PCR
  • Positive in blood for all ATLL subtypes except healthy carriers 1

Chemistry and Metabolic Markers

• Hypercalcemia: Present in acute and lymphoma subtypes; absent in chronic/smoldering 1
• Serum LDH: 1
  • Normal in smoldering
  • <1.5× normal in smoldering
  • <2× normal in chronic

  • 2× normal in acute and lymphoma subtypes

• Comprehensive metabolic panel including electrolytes, BUN, creatinine 1

Bone Marrow Evaluation

• Generally not required for diagnosis when peripheral blood shows characteristic findings 1
• Bone marrow involvement is an independent poor prognostic factor when present 1
• Bone marrow aspirate and biopsy recommended for complete staging 1

Tissue Biopsy (When Indicated)

Excisional lymph node biopsy or tissue biopsy required when diagnosis cannot be established from peripheral blood molecular assays, particularly in lymphoma subtype. 1

• Lymph node biopsy (excisional preferred) 1
• Skin biopsy for cutaneous lesions 1
• GI tract biopsy (upper endoscopy recommended due to frequent GI involvement) 1
• Required for histology and molecular analysis of HTLV-1 provirus integration 1
• Also helps rule out underlying infections (tuberculosis, histoplasmosis, toxoplasmosis) 1

Imaging and Additional Workup

• CT scans: Neck, thorax, abdomen, pelvis 1
• Skeletal survey: In symptomatic patients 1
• CNS evaluation: CT/MRI and/or lumbar puncture in all acute or lymphoma subtypes, or with neurologic symptoms 1
• Stool examination for parasites 1

Critical Diagnostic Pitfalls

The most critical pitfall is failing to test for HTLV-1 serology in patients with peripheral T-cell lymphoma, as this completely changes the diagnosis and management from PTCL-NOS to ATLL. 1 HTLV-1 positivity leads to alternate diagnosis and management compared to standard PTCL treatment approaches 1.

Another common error is relying solely on peripheral blood findings in the lymphoma subtype, where circulating abnormal cells may be <1%, necessitating tissue biopsy for diagnosis. 1