Definition/General
Introduction:
T-Cell Prolymphocytic Leukemia (T-PLL) is a rare, aggressive mature T-cell neoplasm characterized by proliferation of medium-sized prolymphocytes
It represents 2% of mature lymphocytic leukemias in adults over 30 years
T-PLL has a rapidly progressive clinical course with poor prognosis
The disease shows distinctive morphologic and immunophenotypic features.
Origin:
Arises from mature post-thymic T-lymphocytes with memory cell phenotype
The cells show clonal T-cell receptor rearrangement
Most cases express TCL1 protein due to chromosomal rearrangements
ATM gene mutations are present in majority of cases
The neoplastic cells have activated T-cell characteristics with high proliferative activity.
Classification:
WHO classification recognizes T-PLL as distinct entity under mature T-cell neoplasms
Morphologic variants include: Typical T-PLL (most common form - 75%)
Small cell variant (20% of cases)
Cerebriform variant (5% of cases)
All variants share similar immunophenotype and genetics.
Epidemiology:
Very rare disease with incidence 0.6 per million per year
Median age 65 years (range 30-94 years)
Male predominance 2:1
More common in Western countries
Rare in Asian populations including India
Associated with ataxia telangiectasia (AT) in younger patients
Aggressive course with median survival 7-12 months without treatment.
Clinical Features
Presentation:
High white blood cell count (median 100,000-300,000/μL)
Progressive lymphadenopathy (generalized - 70% cases)
Splenomegaly (massive - 80% cases)
Hepatomegaly (60% cases)
Skin infiltration (25-30% cases)
Central nervous system involvement (10-15% cases).
Symptoms:
Rapid clinical deterioration over weeks to months
B-symptoms (fever, night sweats, weight loss - 50% cases)
Skin rash and nodules (T-PLL specific)
Neurologic symptoms (headache, confusion, cranial nerve palsies)
Abdominal distension (hepatosplenomegaly)
Lymph node pain (rapid enlargement).
Risk Factors:
Ataxia telangiectasia (hereditary syndrome with AT gene mutations)
Male gender (2-fold increased risk)
Advanced age (>60 years)
Family history of AT
Previous radiation exposure (weak association)
Immunodeficiency states
No clear environmental factors identified.
Screening:
No routine screening recommendations
Suspect in patients with rapidly progressive lymphocytosis
Consider in AT patients developing lymphocytosis
Flow cytometry essential for diagnosis
TCL1 expression by immunohistochemistry
Cytogenetics for inv(14) or t(14;14).
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Gross Description
Appearance:
Generalized lymphadenopathy with nodes 3-10 cm in diameter
Massive splenomegaly (weight 1000-4000g, normal 150-200g)
Hepatomegaly with smooth, enlarged surface
Skin nodules and plaques (reddish-brown lesions)
Normal to minimally enlarged thymus (unlike T-lymphoblastic lymphoma).
Characteristics:
Lymph nodes show complete architectural effacement
Homogeneous tan-white cut surface without necrosis
Spleen shows massive red pulp expansion
White pulp obliteration by leukemic infiltration
Liver shows hepatomegaly with infiltration
Skin lesions show dermal infiltration.
Size Location:
Lymph nodes: Multiple sites involved (cervical, axillary, inguinal, mediastinal, abdominal)
Spleen: Extends 10-20 cm below left costal margin
Liver: Extends 5-10 cm below right costal margin
Skin lesions variable size (papules to large plaques)
Bone marrow shows hypercellularity.
Multifocality:
Systemic disease with multi-organ involvement
Leukemic phase with high circulating cell count
Nodal and extranodal involvement common
CNS involvement in 10-15% cases
GI tract may be involved
Bone marrow infiltration universal.
Microscopic Description
Histological Features:
T-PLL cells are medium-sized lymphocytes (10-15 μm diameter)
Round to irregular nuclei with prominent nucleoli
Basophilic cytoplasm with occasional blebs and projections
High mitotic activity with frequent mitoses
Diffuse infiltrative pattern in tissues
Vascular invasion may be present.
Cellular Characteristics:
Typical variant: round nuclei with prominent nucleoli and moderate cytoplasm
Small cell variant: smaller cells with less prominent nucleoli
Cerebriform variant: irregular, convoluted nuclei resembling Sézary cells
Chromatin pattern finely dispersed
Cytoplasmic projections in some cells.
Architectural Patterns:
Lymph nodes show complete effacement of normal architecture
Diffuse infiltration with loss of sinusoidal pattern
Spleen shows red pulp infiltration with white pulp atrophy
Bone marrow shows interstitial and focal infiltration
Perivascular infiltration in skin lesions.
Grading Criteria:
No formal grading system for T-PLL
Proliferation index typically high (Ki-67 >50%)
Morphologic variants do not affect prognosis significantly
Blast transformation rare but reported
Degree of tissue infiltration correlates with disease burden.
Immunohistochemistry
Positive Markers:
CD2, CD3, CD7 (pan-T-cell markers positive)
CD4+CD8- (helper T-cell phenotype in 60% cases)
CD4+CD8+ (double positive in 25% cases)
CD4-CD8+ (cytotoxic phenotype in 15% cases)
TCL1 strongly positive (characteristic)
CD52 positive (therapeutic target)
CD25 positive in most cases.
Negative Markers:
CD1a negative (distinguishes from T-lymphoblastic lymphoma)
TdT negative (mature T-cell phenotype)
CD10 negative
CD20, CD79a negative (B-cell markers)
CD56 usually negative (may be positive in some cases)
EBER negative (not EBV-associated).
Diagnostic Utility:
Key immunophenotype: CD3+, CD7+, TCL1+, CD52+
TCL1 positivity highly characteristic (>95% cases)
CD4/CD8 expression patterns variable but don't affect prognosis
Loss of CD7 may occur during disease progression
Aberrant marker expression common.
Molecular Subtypes:
TCL1A gene rearrangements in 80% cases [inv(14)(q11;q32.1) or t(14;14)]
MTCP1 gene rearrangements in 20% cases [t(X;14)]
Both result in TCL1 family protein overexpression
ATM mutations present in >75% cases
JAK/STAT pathway activation common.
Molecular/Genetic
Genetic Mutations:
ATM gene mutations in 75-80% of T-PLL cases (tumor suppressor loss)
TCL1A rearrangements [inv(14)(q11;q32.1)] in 80% cases
MTCP1 rearrangements [t(X;14)(q28;q11)] in 20% cases
TP53 mutations in 30-40% cases
JAK3 mutations in 10-15% cases
Complex karyotype in most cases.
Molecular Markers:
TCL1 protein overexpression (oncogene activation)
ATM protein loss by immunohistochemistry
Clonal TCR rearrangements (monoclonal T-cell population)
Chromosome 14 abnormalities involving TCR loci
Complex cytogenetic abnormalities
High genomic instability.
Prognostic Significance:
TP53 mutations associated with worse prognosis
Complex karyotype indicates aggressive disease
High LDH levels correlate with tumor burden
CNS involvement indicates poor prognosis
Skin involvement may predict better response to alemtuzumab
Age >65 years associated with shorter survival.
Therapeutic Targets:
CD52 targeted by alemtuzumab (anti-CD52 monoclonal antibody)
JAK/STAT pathway inhibitors in development
ATM pathway synthetic lethality approaches
BCL2 inhibitors may be effective
Allogeneic stem cell transplant for eligible patients
CAR-T cell therapy under investigation.
Differential Diagnosis
Similar Entities:
Adult T-cell Leukemia/Lymphoma (HTLV-1 associated)
Sézary Syndrome (cutaneous T-cell lymphoma)
Peripheral T-cell Lymphoma, NOS
Large Granular Lymphocytic Leukemia
T-lymphoblastic Leukemia/Lymphoma
Chronic Lymphocytic Leukemia (rare T-cell variant).
Distinguishing Features:
T-PLL: TCL1+, CD52+, aggressive course, prolymphocyte morphology
ATL: HTLV-1+, geographic distribution, flower cells
Sézary: Cutaneous involvement, cerebriform nuclei, CD7-
PTCL: TCL1-, different immunophenotype
T-LGL: Cytotoxic markers, indolent course, neutropenia.
Diagnostic Challenges:
Distinguishing T-PLL from ATL (HTLV-1 serology essential)
Cerebriform variant versus Sézary syndrome (clinical presentation, TCL1 expression)
Small cell variant versus CLL (immunophenotype, TCL1)
Secondary T-PLL from other T-cell neoplasms
Reactive T-cell proliferation in immunocompromised patients.
Rare Variants:
Secondary T-PLL transformation from other T-cell lymphomas
T-PLL with t(X;14) (MTCP1 rearrangement)
Therapy-related T-PLL (post-chemotherapy/radiation)
T-PLL in ataxia telangiectasia patients
Blastic transformation of T-PLL (rare).
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
Peripheral blood, lymph node biopsy, bone marrow aspirate and biopsy
Peripheral Blood Findings
Marked lymphocytosis ([count]/μL) with prolymphocyte morphology
Cell Morphology
Medium-sized lymphocytes with round nuclei, prominent nucleoli, and basophilic cytoplasm
Tissue Findings
Diffuse infiltration with complete architectural effacement
Flow Cytometry/Immunohistochemistry
CD3+, CD7+, TCL1+, CD52+, [CD4/CD8 status]
Cytogenetic Analysis
[karyotype] with TCL1 rearrangements: [inv(14)/t(14;14)/t(X;14)]
Molecular Studies
ATM mutations: [detected/not detected], TP53 status: [result]
Clinical Staging
Stage [I-IV] with [organ involvement details]
Prognostic Factors
Age: [X] years, LDH: [level], CNS involvement: [present/absent]
Final Diagnosis
T-Cell Prolymphocytic Leukemia, [typical/small cell/cerebriform] variant