Definition/General
Introduction:
Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in Western adults, characterized by clonal proliferation of mature-appearing B-lymphocytes
It is identical to Small Lymphocytic Lymphoma (SLL) except for the degree of peripheral blood involvement.
Origin:
Arises from mature B-cells that are arrested in differentiation
Cells accumulate due to defective apoptosis rather than increased proliferation
May arise from marginal zone or follicular mantle.
Classification:
WHO Classification: Same disease as SLL
Diagnosis requires ≥5000 clonal B-lymphocytes/μL in blood
Binet and Rai staging systems used
ZAP-70 and IGHV mutation status important.
Epidemiology:
Median age 65-70 years
Male predominance (2:1)
Most common leukemia in Western adults
Rare in Asia and Africa
Strong familial clustering (genetic predisposition).
Clinical Features
Presentation:
Lymphocytosis (>5000/μL)
Painless lymphadenopathy (60%)
Splenomegaly (50%)
Hepatomegaly (20%)
Often asymptomatic at diagnosis (25%).
Symptoms:
Often asymptomatic
Fatigue and weakness
Recurrent infections
B-symptoms (fever, night sweats, weight loss) - uncommon
Easy bruising (thrombocytopenia).
Risk Factors:
Family history (strongest risk factor)
Advanced age
Male gender
Caucasian ethnicity
Environmental factors unclear.
Screening:
Diagnosed by peripheral blood count and smear
Flow cytometry confirms diagnosis
Staging by physical exam and imaging
Bone marrow biopsy usually not required.
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Gross Description
Appearance:
Enlarged lymph nodes with homogeneous gray-white cut surface
Soft consistency
Bone marrow may appear hypercellular
Spleen shows white pulp expansion.
Characteristics:
Lymph nodes typically 2-5 cm
Soft, rubbery consistency
Homogeneous appearance
Capsule intact
Splenomegaly common.
Size Location:
Generalized lymphadenopathy
Cervical, axillary, inguinal nodes involved
Bone marrow involvement universal
Extranodal sites rare initially.
Multifocality:
Systemic disease by definition
Involves blood, bone marrow, lymph nodes, spleen
Liver involvement possible
CNS involvement rare.
Microscopic Description
Histological Features:
Small mature lymphocytes with clumped chromatin and scanty cytoplasm
Prolymphocytes (<55% for CLL diagnosis)
Smudge cells characteristic on blood smear.
Cellular Characteristics:
Small lymphocytes (8-12 μm)
Round to slightly irregular nuclei
Clumped chromatin
Inconspicuous nucleoli
Scanty blue cytoplasm
Fragile cells (smudge cells).
Architectural Patterns:
Diffuse infiltration in bone marrow and lymph nodes
Pseudofollicular proliferation centers in lymph nodes
Parasinusoidal pattern in bone marrow possible.
Immunohistochemistry
Positive Markers:
CD19 positive
CD20 positive (dim)
CD5 positive (co-expression diagnostic)
CD23 positive
BCL2 positive
Surface immunoglobulin weak.
Negative Markers:
CD10 negative
FMC7 negative (usually)
Cyclin D1 negative
CD103 negative
Annexin A1 negative.
Diagnostic Utility:
CD5+/CD23+ B-cell phenotype highly characteristic
Flow cytometry shows monoclonal B-cells
LEF1 nuclear staining in tissue sections.
Molecular Subtypes:
ZAP-70 positive (unfavorable) vs negative (favorable)
IGHV mutated (favorable) vs unmutated (unfavorable)
CD38 expression correlates with prognosis.
Molecular/Genetic
Genetic Mutations:
del(13q14) most common (50%)
Trisomy 12 (15%)
del(11q22-23) ATM gene (15%)
del(17p13) TP53 gene (5%)
NOTCH1 mutations.
Molecular Markers:
IGHV mutation status most important prognostic factor
ZAP-70 expression correlates with IGHV
β2-microglobulin elevated
Clonal immunoglobulin rearrangements.
Prognostic Significance:
IGHV mutated: indolent course
IGHV unmutated: aggressive course
del(17p) and TP53 mutations: poor prognosis
del(13q) alone: favorable.
Therapeutic Targets:
BTK inhibitors (ibrutinib, acalabrutinib)
BCL2 inhibitors (venetoclax)
CD20-targeted therapy (rituximab)
PI3K inhibitors.
Differential Diagnosis
Similar Entities:
Hairy cell leukemia
Prolymphocytic leukemia
Mantle cell lymphoma
Marginal zone lymphoma
Large granular lymphocyte leukemia
Reactive lymphocytosis.
Distinguishing Features:
CLL: CD5+/CD23+/weak sIg
MCL: CD5+/CD23-/Cyclin D1+
HCL: CD103+/TRAP+/hairy projections
PLL: >55% prolymphocytes.
Diagnostic Challenges:
Distinction from MCL (especially CD23+ cases)
Recognition of Richter transformation
Atypical CLL variants.
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
Complete Blood Count
WBC: [X]/μL, Lymphocytes: [X]/μL (>5000 for CLL diagnosis)
Morphological Features
Small mature lymphocytes with clumped chromatin, smudge cells present
Flow Cytometry
Monoclonal B-cell population: CD19+, CD20+ (dim), CD5+, CD23+, weak surface immunoglobulin
Cytogenetics
FISH: [del(13q14)/trisomy 12/del(11q)/del(17p)], Karyotype: [if performed]
Molecular Studies
IGHV mutation status: [mutated/unmutated], ZAP-70: [positive/negative]
Prognostic Markers
β2-microglobulin: [X], CD38: [X]%, ZAP-70: [X]%
Staging
Rai stage: [0/I/II/III/IV], Binet stage: [A/B/C]
Risk Stratification
Risk group: [Low/Intermediate/High] based on cytogenetics and molecular markers
Final Diagnosis
Final diagnosis: Chronic Lymphocytic Leukemia, [Rai/Binet stage], [risk group]