Definition/General
Introduction:
Prolymphocytic Leukemia (PLL) is a rare aggressive lymphoproliferative disorder characterized by circulating prolymphocytes
It comprises B-cell PLL (B-PLL) and T-cell PLL (T-PLL) variants
PLL represents 1-2% of all lymphoid leukemias
The disease is defined by >55% prolymphocytes in peripheral blood.
Origin:
B-PLL arises from mature B-lymphocytes with post-germinal center phenotype
T-PLL originates from mature T-lymphocytes with post-thymic differentiation
Both variants show aggressive clinical behavior
The prolymphocytes are larger than small lymphocytes with prominent nucleoli and abundant cytoplasm.
Classification:
WHO classification recognizes two main types: B-cell Prolymphocytic Leukemia (B-PLL) and T-cell Prolymphocytic Leukemia (T-PLL)
B-PLL accounts for 80% of PLL cases
T-PLL represents 20% of PLL cases
Both require >55% prolymphocytes in peripheral blood for diagnosis.
Epidemiology:
Very rare disease with incidence <0.1 per 100,000 per year
Elderly predominance with median age 65-70 years
Male predominance in both B-PLL and T-PLL (2:1 ratio)
B-PLL more common in Western populations
T-PLL shows no ethnic predilection
Aggressive course with poor prognosis.
Clinical Features
Presentation:
Massive splenomegaly (present in >90% cases)
High white blood cell count (typically >100,000/μL)
Minimal lymphadenopathy (distinguishes from CLL)
Hepatomegaly in 50-60% cases
B-symptoms (fever, night sweats, weight loss) in 30-40%
Skin infiltration more common in T-PLL.
Symptoms:
Progressive fatigue and weakness (90% cases)
Abdominal distension due to splenomegaly
Early satiety from splenic enlargement
Constitutional symptoms (weight loss, fever)
Skin lesions (especially in T-PLL)
Recurrent infections due to immunosuppression.
Risk Factors:
Advanced age (>60 years)
Male gender (2-fold increased risk)
Previous CLL (B-PLL may transform from CLL)
Immunosuppression (weak association)
No radiation exposure association
No familial clustering reported
No viral associations established.
Screening:
No routine screening recommendations
Suspect in elderly patients with marked leukocytosis and splenomegaly
Consider in patients with CLL transformation
Complete blood count shows high WBC with prolymphocytes
Flow cytometry essential for diagnosis
Morphology review confirms prolymphocyte percentage.
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Gross Description
Appearance:
Massive splenomegaly (weight 1000-5000g, normal 150-200g)
Spleen has smooth capsule with dark red, congested cut surface
Mild hepatomegaly in 50-60% cases
Lymphadenopathy minimal or absent (key differentiating feature)
Bone marrow hypercellularity on biopsy.
Characteristics:
Spleen shows red pulp expansion with infiltrating prolymphocytes
White pulp preservation (unlike hairy cell leukemia)
Liver shows portal and sinusoidal infiltration pattern
Lymph nodes when involved show diffuse architecture effacement
Bone marrow shows patchy to diffuse infiltration.
Size Location:
Spleen extends 15-25 cm below left costal margin in most cases
Can extend to pelvis in extreme cases
Liver enlargement typically 3-8 cm below right costal margin
Lymph node enlargement <5 cm when present
Bone marrow cellularity 80-95%.
Multifocality:
Leukemic phase with high circulating cell count
Splenic involvement universal and massive
Hepatic infiltration common but less prominent
Bone marrow involvement in all cases
Extranodal sites: skin (T-PLL), CNS (rare), GI tract (rare).
Microscopic Description
Histological Features:
Prolymphocytes are larger than small lymphocytes (15-20 μm diameter)
Round to oval nuclei with vesicular chromatin
Single prominent nucleolus (defining feature)
Moderate amount of basophilic cytoplasm
High nuclear-cytoplasmic ratio
Mitotic activity variable but usually low.
Cellular Characteristics:
B-PLL cells have central prominent nucleolus and moderate cytoplasm
T-PLL cells may have irregular nuclear contours and cerebriform nuclei
Chromatin pattern more dispersed than small lymphocytes
Cytoplasm shows moderate basophilia
Occasional binucleated forms may be present.
Architectural Patterns:
Bone marrow shows diffuse or interstitial infiltration
Spleen shows red pulp infiltration preserving white pulp architecture
Liver shows portal and sinusoidal infiltration pattern
Pseudofollicular pattern may occur in lymph nodes
Increased reticulin in bone marrow (mild).
Grading Criteria:
Diagnosis requires >55% prolymphocytes in peripheral blood
Mixed forms with 11-54% prolymphocytes require specific designation
Transformation criteria from CLL include new cytogenetic abnormalities
Blast transformation defined as >20% blasts
Richter transformation possible in B-PLL.
Immunohistochemistry
Positive Markers:
B-PLL: CD19, CD20, CD22 (pan-B-cell markers positive)
CD79a and CD79b positive
Strong sIg expression (IgM or IgG)
FMC7 positive (unlike CLL)
T-PLL: CD2, CD3, CD7 (pan-T-cell markers)
CD52 strongly positive in T-PLL
TCL1 positive in most T-PLL cases.
Negative Markers:
B-PLL: CD5 and CD23 usually negative (unlike CLL)
CD10 negative (unlike follicular lymphoma)
Cyclin D1 negative (unlike mantle cell lymphoma)
T-PLL: CD1a and CD99 negative (mature T-cell phenotype)
CD4/CD8 may be negative or show aberrant expression.
Diagnostic Utility:
B-PLL immunophenotype: CD19+, CD20+, CD5-, CD23-, FMC7+, strong sIg+
T-PLL immunophenotype: CD2+, CD3+, CD7+, CD52+, TCL1+
Flow cytometry essential for accurate phenotyping
CD38 expression variable
ZAP70 may be positive in B-PLL (prognostic significance).
Molecular Subtypes:
B-PLL may arise de novo or from CLL transformation
T-PLL shows characteristic TCR gene rearrangements
TP53 mutations common in both variants (poor prognosis)
ATM mutations frequent in T-PLL
NOTCH1 mutations may occur in transformation from CLL.
Molecular/Genetic
Genetic Mutations:
B-PLL: TP53 mutations in 50-75% cases (associated with poor prognosis)
ATM mutations in 30-40% cases
MYC rearrangements in 20-30% cases
T-PLL: ATM mutations in 80-90% cases (characteristic)
TCL1 rearrangements in 80% cases
MTCP1 rearrangements in 20% T-PLL cases.
Molecular Markers:
Clonal immunoglobulin rearrangements in B-PLL
TCR gene rearrangements in T-PLL
TP53 dysfunction common in both types
Complex karyotype frequent
ATM protein loss by immunohistochemistry in T-PLL
TCL1 overexpression characteristic of T-PLL.
Prognostic Significance:
TP53 mutations predict poor response to therapy
Complex karyotype associated with aggressive course
High LDH levels indicate poor prognosis
ATM status affects treatment response
Prolymphocyte percentage correlates with outcome
ZAP70 expression may predict aggressive behavior.
Therapeutic Targets:
B-PLL: Anti-CD20 antibodies (rituximab, ofatumumab)
BTK inhibitors (ibrutinib) effective
PI3K inhibitors (idelalisib) may be beneficial
T-PLL: Anti-CD52 antibodies (alemtuzumab) highly effective
Purine analogues have limited efficacy
Allogeneic stem cell transplant for eligible patients.
Differential Diagnosis
Similar Entities:
Chronic Lymphocytic Leukemia (CLL): CD5+, CD23+, different morphology
Mantle Cell Lymphoma: CD5+, cyclin D1+, different clinical presentation
Follicular Lymphoma: CD10+, bcl-2+, nodal presentation
Large Granular Lymphocytic Leukemia: cytotoxic markers, different morphology
Adult T-cell Leukemia: HTLV-1+, different geographic distribution.
Distinguishing Features:
PLL: >55% prolymphocytes, prominent nucleoli, minimal lymphadenopathy
CLL: CD5+, CD23+, small lymphocytes, lymphadenopathy
MCL: Cyclin D1+, nodal presentation, different age
FL: CD10+, bcl-2+, follicular pattern
LGL: Large granules, CD57+, cytotoxic markers.
Diagnostic Challenges:
Distinguishing B-PLL from CLL with prolymphocytes (prolymphocyte percentage)
T-PLL versus mature T-cell lymphomas with leukemic presentation
De novo versus transformed PLL (clinical and molecular differences)
Mixed prolymphocytic/lymphocytic populations (intermediate cases)
Reactive prolymphocytosis in viral infections.
Rare Variants:
B-PLL with t(11;14): cyclin D1 positive variant
T-PLL with complex karyotype: particularly aggressive
Mixed B/T-PLL: extremely rare biphenotypic cases
PLL transformation from other lymphomas
Secondary PLL after chemotherapy (therapy-related).
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, bone marrow aspirate and biopsy, [date collected]
Peripheral Blood Findings
WBC: [count]/μL with [X]% prolymphocytes (>55% required for diagnosis)
Cell Morphology
Large lymphoid cells with prominent nucleoli and moderate cytoplasm
Bone Marrow Findings
[X]% cellularity with [diffuse/interstitial] infiltration by prolymphocytes
Flow Cytometry
[B-cell/T-cell] immunophenotype: [specific markers and results]
Cytogenetic Analysis
[karyotype] with [specific abnormalities if present]
Molecular Studies
[TP53/ATM/other mutations]: [detected/not detected]
Additional Studies
Immunohistochemistry: [if performed]
FISH: [if performed]
[other studies]: [results]
Final Diagnosis
[B-cell/T-cell] Prolymphocytic Leukemia