Definition/General
Introduction:
Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm caused by human T-lymphotropic virus type 1 (HTLV-1) infection
It represents a unique virus-associated malignancy with characteristic morphological and clinical features
The disease shows geographic clustering in HTLV-1 endemic areas
Four clinical subtypes are recognized with varying prognosis
Hypercalcemia and immunosuppression are common complications.
Origin:
Originates from HTLV-1 infected mature T-lymphocytes that have undergone malignant transformation
HTLV-1 proviral DNA integration into host T-cell genome is pathognomonic
Tax and HBZ viral proteins drive oncogenesis
Shows clonal T-cell receptor gene rearrangements
Helper T-cell phenotype (CD4+) predominant
Long latency period (decades) from infection to malignancy
Adult T-cell subset preferentially infected.
Classification:
WHO classification recognizes four clinical subtypes: Acute ATLL (most aggressive, poor prognosis)
Lymphomatous ATLL (nodal disease without leukemia)
Chronic ATLL (indolent course with skin involvement)
Smoldering ATLL (most indolent, limited disease)
Histological variants include pleomorphic, immunoblastic, and anaplastic
Grade not applicable due to clinical subtype classification.
Epidemiology:
Geographic clustering in HTLV-1 endemic areas (Japan, Caribbean, Central Africa, Iran, Romania)
Adult onset (median age 40-60 years)
Equal gender distribution or slight male predominance
Rare in India except among certain tribal populations
Mother-to-child transmission most common route
Lifetime risk of ATLL development 2-5% in HTLV-1 carriers
Long latency (20-60 years) from infection.
Clinical Features
Presentation:
Clinical subtype-dependent presentation
Acute: leukemia, hypercalcemia, organomegaly
Lymphomatous: lymphadenopathy without leukemia
Chronic: skin lesions, mild lymphocytosis
Smoldering: minimal symptoms, <5% abnormal cells
Hypercalcemia in 50-70% of acute cases
Opportunistic infections due to immunosuppression.
Symptoms:
Constitutional symptoms (fever, weight loss, night sweats)
Hypercalcemia symptoms (polyuria, polydipsia, confusion)
Skin manifestations (erythroderma, nodules, tumors)
Neurological symptoms (confusion, coma from hypercalcemia)
Gastrointestinal symptoms (nausea, vomiting)
Bone pain (lytic lesions)
Recurrent infections (opportunistic pathogens).
Risk Factors:
HTLV-1 seropositivity (essential risk factor)
Geographic residence in endemic areas
Mother-to-child transmission (breastfeeding)
Sexual transmission (less common)
Blood transfusion (rare with screening)
Intravenous drug use (needle sharing)
Family history of HTLV-1 infection
Age >40 years (increased risk with age).
Screening:
HTLV-1 serology (anti-HTLV-1 antibodies)
HTLV-1 proviral DNA by PCR
Complete blood count with peripheral smear
Serum calcium levels (hypercalcemia)
Flow cytometry of abnormal T-cells
Imaging studies for staging
Bone marrow examination if indicated
CSF examination for CNS involvement.
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Gross Description
Appearance:
Lymph node enlargement in lymphomatous type
Hepatosplenomegaly in acute type
Skin lesions range from erythematous patches to tumors
Lytic bone lesions may be present
CNS involvement may cause mass lesions
Pleural effusions and ascites in advanced cases.
Characteristics:
Lymph nodes: enlarged, firm, gray-white cut surface
Spleen: enlarged with white pulp involvement
Liver: hepatomegaly with portal infiltration
Skin lesions: erythroderma, plaques, tumors
Bone lesions: lytic with soft tissue extension
Multiple organ involvement in acute disease.
Size Location:
Lymph nodes: 2-10 cm in lymphomatous type
Spleen: moderate to massive enlargement
Liver: mild to moderate enlargement
Skin lesions: variable size and distribution
Bone lesions: multiple sites (skull, spine, pelvis)
CNS lesions: variable size and location.
Multifocality:
Systemic disease in most cases
Multiple organ involvement characteristic
Leukemic phase in acute and chronic types
Lymphomatous masses in lymphomatous type
Skin involvement common in chronic type
Bone marrow involvement frequent
CNS involvement in advanced cases.
Microscopic Description
Histological Features:
Pleomorphic T-cell infiltrate with variable morphology
Flower cells (multilobated nuclei resembling flowers) pathognomonic
Medium to large cells with irregular nuclear contours
Prominent nucleoli
Mitotic activity variable
Tissue infiltration pattern varies by organ
Associated inflammatory cells (eosinophils, histiocytes).
Cellular Characteristics:
Flower cells: multilobated nuclei with deep indentations
Pleomorphic lymphoid cells of medium to large size
Convoluted nuclear contours
Vesicular to hyperchromatic chromatin
Prominent nucleoli in large cells
Moderate to abundant cytoplasm
High nuclear-cytoplasmic ratio
Frequent mitoses in aggressive variants.
Architectural Patterns:
Diffuse infiltration pattern most common
Paracortical expansion in lymph nodes
Sinusoidal infiltration in liver and spleen
Perivascular distribution in various organs
Epidermotropism in skin involvement
Leptomeningeal infiltration in CNS involvement
Bone marrow infiltration pattern variable.
Grading Criteria:
Clinical subtype more important than histological grade
Acute type: high-grade morphology with large cells
Chronic type: low-grade morphology with small cells
Proliferation index (Ki-67) varies by subtype
Large cell transformation may occur
Anaplastic features in some cases
Immunoblastic morphology in subset.
Immunohistochemistry
Positive Markers:
CD3 (pan-T-cell marker, positive)
CD4 (positive in >90% cases)
CD2 (usually positive)
CD5 (may be lost)
CD25 (IL-2 receptor, strongly positive)
CD30 (may be positive in large cells)
FOXP3 (regulatory T-cell marker, often positive)
CCR4 (chemokine receptor, positive).
Negative Markers:
CD7 (frequently lost)
CD8 (negative in typical cases)
CD20 (B-cell marker, negative)
ALK (negative)
CD56 (NK marker, negative)
TIA-1 and Granzyme B (cytotoxic markers, negative)
CD10 (negative)
BCL6 (negative in T-cells).
Diagnostic Utility:
CD25 overexpression characteristic feature
Loss of CD7 supports neoplastic nature
FOXP3 positivity indicates regulatory T-cell phenotype
CD4+ helper phenotype predominant
Ki-67 varies by clinical subtype
HTLV-1 Tax protein detection possible but not routine
Flow cytometry helpful for circulating cells.
Molecular Subtypes:
Helper T-cell phenotype (CD4+, CD25+) predominant
Regulatory T-cell features (FOXP3+)
Activated phenotype (CD25 high)
Loss of T-cell antigens (CD7, CD5) common
Cytotoxic phenotype rare (CD8+)
Anaplastic variant (CD30+)
Large cell variant with different immunoprofile.
Molecular/Genetic
Genetic Mutations:
HTLV-1 proviral DNA integration (pathognomonic)
Clonal T-cell receptor rearrangements
TP53 mutations in aggressive variants
CDKN2A/B deletions
IRF4 overexpression
CCR4 overexpression
PLCG1 mutations in some cases
Complex chromosomal abnormalities in acute type.
Molecular Markers:
HTLV-1 Tax protein drives transformation
HTLV-1 HBZ protein (oncogenic)
IL-2 receptor overexpression (CD25)
NF-κB pathway activation
JAK/STAT pathway dysregulation
Cell cycle dysregulation
Apoptosis resistance
Telomerase activation.
Prognostic Significance:
Clinical subtype most important prognostic factor
Acute type: median survival 6-10 months
Lymphomatous type: median survival 10-12 months
Chronic type: median survival 2+ years
Smoldering type: indolent course, may transform
Hypercalcemia indicates poor prognosis
CNS involvement indicates poor prognosis.
Therapeutic Targets:
Combination chemotherapy (CHOP-like regimens)
Anti-CCR4 monoclonal antibody (mogamulizumab)
Antiviral therapy (zidovudine + interferon-α)
Proteasome inhibitors (bortezomib)
Hypercalcemia management (bisphosphonates)
Allogeneic stem cell transplant in selected cases
Novel agents under investigation.
Differential Diagnosis
Similar Entities:
Other T-cell lymphomas (PTCL-NOS, AITL, ALCL)
Sézary syndrome (erythroderma with leukemia)
Chronic lymphocytic leukemia (mature lymphoid cells)
Large granular lymphocyte leukemia
Reactive T-cell disorders
HTLV-1 carriers without malignancy
Tropical spastic paraparesis (HTLV-1 associated).
Distinguishing Features:
ATLL: HTLV-1+, flower cells, CD25+, hypercalcemia
Other TCL: HTLV-1-, different morphology and immunoprofile
Sézary syndrome: cerebriform nuclei, HTLV-1-
CLL: CD5+, CD23+, different morphology
HTLV-1 carriers: polyclonal, no malignant features
Molecular testing for HTLV-1 proviral DNA crucial.
Diagnostic Challenges:
HTLV-1 serology vs proviral DNA detection
Distinguishing subtypes requires clinical correlation
Reactive vs neoplastic in HTLV-1 carriers
Morphological overlap with other T-cell lymphomas
Limited tissue may prevent full characterization
Geographic considerations for HTLV-1 endemic areas.
Rare Variants:
Primary cutaneous ATLL
CNS ATLL (primary or secondary)
Composite lymphomas (ATLL with other lymphomas)
Transformation from smoldering to acute
Hypodiploid ATLL
ATLL with plasmacytic differentiation
Anaplastic large cell variant.
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
[Specimen type] from [anatomical site], HTLV-1 status: positive
Primary Diagnosis
Adult T-cell leukemia/lymphoma, [clinical subtype]
WHO Classification
Adult T-cell leukemia/lymphoma (WHO 2016)
Clinical Subtype
Clinical subtype: [acute/lymphomatous/chronic/smoldering]
Histological Features
Shows pleomorphic T-cell infiltrate with characteristic flower cells (multilobated nuclei)
Cellular Morphology
Flower cells with multilobated nuclei; Cell size: [small/medium/large]; Pleomorphism: [mild/moderate/marked]
Immunohistochemistry
CD3+, CD4+, CD25+ (strong), CD7- (loss), CD20-, Ki-67: [percentage]%
HTLV-1 Studies
HTLV-1 serology: positive; HTLV-1 proviral DNA: [positive/detected by PCR]
Clinical Features
Hypercalcemia: [present/absent]; Organomegaly: [present/absent]; Skin involvement: [present/absent]
Molecular Studies
T-cell receptor rearrangement: clonal; HTLV-1 proviral integration: demonstrated
Final Diagnosis
Adult T-cell leukemia/lymphoma, [clinical subtype], WHO 2016