Definition/General
Introduction:
Sézary syndrome (SS) represents the leukemic phase of cutaneous T-cell lymphoma characterized by the triad of erythroderma, generalized lymphadenopathy, and circulating malignant T-cells (Sézary cells)
It accounts for 2-3% of all cutaneous T-cell lymphomas
The syndrome shows aggressive clinical behavior with poor prognosis
Diagnostic criteria require presence of all three classical features.
Origin:
Originates from mature CD4+ T-helper lymphocytes with skin-homing properties that have disseminated systemically
Shows clonal T-cell receptor gene rearrangements identical in skin and blood
Memory T-cell phenotype (CD45RO+) with regulatory T-cell features
Expresses cutaneous lymphocyte antigen (CLA)
May represent transformation from mycosis fungoides or arise de novo
Immunosuppressive microenvironment contributes to disease progression.
Classification:
WHO-EORTC classification defines as distinct clinical entity within CTCL spectrum
Classical Sézary syndrome with erythroderma and leukemic phase
Relationship to mycosis fungoides complex (may be transformation or separate entity)
Staging follows TNM system with T4 (erythroderma), N0-3, M0-1, B1-2 (blood involvement)
Stage III-IV disease by definition.
Epidemiology:
Incidence 0.1-0.2 cases per million per year
Male predominance (M:F = 2:1)
Peak incidence in 6th-7th decades
Rare disease representing 2-3% of all CTCL
Poor prognosis with median survival 2-4 years
Geographic variation reported
Indian population data limited but shows similar patterns to global incidence.
Clinical Features
Presentation:
Erythroderma (generalized redness >80% body surface area)
Generalized lymphadenopathy (multiple nodal groups)
Circulating Sézary cells in peripheral blood
Intense pruritus with excoriation
Scaling and desquamation
Hair loss (alopecia)
Nail dystrophy
Palmoplantar keratoderma may be present.
Symptoms:
Severe pruritus (universal symptom)
Burning skin sensation
Chills and rigors
Temperature dysregulation
Skin tightness and discomfort
Constitutional symptoms (fever, weight loss, night sweats)
Fatigue and weakness
Secondary bacterial infections
Fluid and electrolyte imbalance.
Risk Factors:
Advanced age (peak 6th-7th decades)
Male gender
Pre-existing mycosis fungoides (transformation)
Immunosuppression (may accelerate progression)
Environmental exposures (chemicals, radiation)
Chronic inflammatory conditions
Genetic predisposition (rare familial cases)
Previous malignancy (rare association).
Screening:
Clinical examination for erythroderma and lymphadenopathy
Complete blood count with differential
Peripheral blood smear for Sézary cells
Flow cytometry of peripheral blood (essential)
Skin biopsy from erythrodermic areas
Lymph node biopsy if enlarged
Staging studies (CT, PET-CT)
Bone marrow biopsy in selected cases.
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Gross Description
Appearance:
Generalized erythroderma with bright red discoloration of skin
Fine to coarse scaling throughout body
Excoriation marks from intense scratching
Lichenification in chronic areas
Leonine facies (facial thickening and coarsening)
Enlarged lymph nodes (rubbery consistency)
Hepatosplenomegaly may be present.
Characteristics:
Confluent erythema involving >80% body surface area
Scaling varies from fine to thick and lamellar
Skin appears taut and indurated
Loss of normal skin markings
Poikiloderma (atrophy, telangiectasia, pigmentation)
Palm and sole involvement
Nail changes (dystrophy, onycholysis).
Size Location:
Generalized involvement by definition (>80% body surface)
Spares mucous membranes typically
Lymphadenopathy involves multiple nodal groups
Node size typically 1-5 cm
Hepatomegaly in 50% of cases
Splenomegaly in 30% of cases
Visceral involvement in advanced cases.
Multifocality:
Systemic disease by definition
Skin involvement is generalized and confluent
Lymph node involvement is multifocal
Blood involvement is characteristic feature
Bone marrow involvement in advanced cases
Visceral organ involvement (liver, spleen, lungs)
CNS involvement is rare but reported.
Microscopic Description
Histological Features:
Epidermotropism may be minimal or absent (unlike mycosis fungoides)
Band-like lymphoid infiltrate in upper dermis
Sézary cells with characteristic cerebriform nuclei in dermis and blood
Minimal spongiosis
Hyperkeratosis and parakeratosis
Acanthosis may be present
Perivascular infiltrate in deeper dermis.
Cellular Characteristics:
Sézary cells are medium to large lymphoid cells
Cerebriform nuclei with deep nuclear convolutions
Hyperchromatic chromatin
Prominent nuclear grooves and lobulations
Scant cytoplasm
Nuclear size >7.5 μm (larger than normal lymphocytes)
Mitotic activity variable
Large cell transformation may occur.
Architectural Patterns:
Band-like dermal infiltrate without significant epidermotropism
Perivascular distribution in superficial and deep dermis
Interstitial pattern of infiltration
Lack of Pautrier microabscesses (unlike mycosis fungoides)
Diffuse dermal involvement
Lymph node architecture may be preserved or effaced.
Grading Criteria:
No formal grading system as considered advanced stage disease
Degree of blood involvement important for diagnosis
Lymph node involvement pattern affects prognosis
Large cell transformation indicates aggressive behavior
Ki-67 proliferation index variable but often elevated
Tumor burden assessment important for monitoring.
Immunohistochemistry
Positive Markers:
CD3 (pan-T-cell marker, positive)
CD4 (positive in >95% of cases)
CD2 (usually positive)
CD5 (may be lost in some cases)
CD45RO (memory T-cell marker)
Cutaneous lymphocyte antigen (CLA)
CCR4 (chemokine receptor)
CD25 (IL-2 receptor, activation marker)
FOXP3 (regulatory T-cell marker, subset positive).
Negative Markers:
CD7 (characteristically lost in >90% cases)
CD8 (negative)
CD20 (B-cell marker, negative)
CD30 (negative except in transformation)
CD56 (NK marker, negative)
TIA-1 and Granzyme B (cytotoxic markers, negative)
ALK (negative)
EBER (EBV marker, negative).
Diagnostic Utility:
Loss of CD7 is crucial diagnostic marker (aberrant phenotype)
CD4+ helper phenotype predominant
Flow cytometry essential for blood involvement assessment
CD4/CD8 ratio >10 in peripheral blood suggestive
Loss of CD26 may be helpful
Clonality assessment by flow cytometry
Ki-67 shows variable proliferation.
Molecular Subtypes:
Classical phenotype (CD4+, CD7-)
Regulatory T-cell features (FOXP3+, CD25+)
Skin-homing phenotype (CLA+, CCR4+)
Large cell transformation (CD30+ in transformed cells)
Rare variants (CD8+, CD4-/CD8-)
Flow cytometry patterns help distinguish from reactive conditions.
Molecular/Genetic
Genetic Mutations:
Clonal T-cell receptor gene rearrangements (identical in skin and blood)
TP53 mutations common (>50% of cases)
CDKN2A deletions (p16 tumor suppressor)
STAT3 and STAT5 mutations
PLCG1 mutations
CARD11 mutations
Complex karyotype with multiple chromosomal abnormalities
PIK3CA mutations.
Molecular Markers:
T-cell receptor clonality in blood and skin
Gene expression profiling shows regulatory T-cell signature
Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13)
Increased IL-10 and TGF-β production
Immunosuppressive microenvironment
MicroRNA dysregulation
Epigenetic modifications
JAK/STAT pathway activation.
Prognostic Significance:
Poor prognosis overall (median survival 2-4 years)
Age >65 years indicates worse outcome
High tumor burden (>20% Sézary cells) associated with poor prognosis
Large cell transformation indicates very poor prognosis
Lymph node involvement pattern affects survival
Elevated LDH indicates poor prognosis
Performance status important prognostic factor.
Therapeutic Targets:
Extracorporeal photopheresis (standard treatment)
Systemic retinoids (bexarotene)
HDAC inhibitors (vorinostat, romidepsin)
Monoclonal antibodies (alemtuzumab, mogamulizumab)
Interferon-α
Chemotherapy (single agent or combination)
Stem cell transplantation in selected patients
Novel agents under investigation.
Differential Diagnosis
Similar Entities:
Erythrodermic mycosis fungoides (T4 stage without leukemic phase)
Adult T-cell leukemia/lymphoma (HTLV-1 positive)
Chronic lymphocytic leukemia with skin involvement
Large granular lymphocyte leukemia
Benign erythroderma (drug-induced, atopic dermatitis)
Other T-cell lymphomas with leukemic phase
Hypereosinophilic syndrome.
Distinguishing Features:
Sézary syndrome: erythroderma + lymphadenopathy + blood involvement, CD4+, CD7-
Erythrodermic MF: lacks significant blood involvement
ATLL: HTLV-1+, flower cells, hypercalcemia
CLL: CD5+, CD23+, different morphology
Benign erythroderma: polyclonal, lacks atypical cells
Flow cytometry and molecular studies crucial.
Diagnostic Challenges:
Distinguishing from erythrodermic MF without blood involvement
Reactive erythroderma with circulating activated T-cells
Low-level blood involvement may be difficult to detect
Morphological overlap with other T-cell disorders
Clonality assessment may be challenging
Need for integrated approach combining clinical, morphological, and molecular features.
Rare Variants:
Sézary syndrome with large cell transformation
CD8+ Sézary syndrome (rare variant)
Double-negative Sézary syndrome (CD4-, CD8-)
Composite lymphomas (extremely rare)
Transformation to other lymphomas
Plasma cell differentiation (rare)
CNS involvement (rare complication).
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
Skin biopsy from erythrodermic area and peripheral blood analysis
Primary Diagnosis
Sézary syndrome
WHO-EORTC Classification
Sézary syndrome (WHO-EORTC classification)
Clinical Features
Erythroderma: [percentage]% body surface; Lymphadenopathy: [present/absent]; Blood involvement: [present]
Peripheral Blood Findings
Sézary cells: [count/μL or percentage]; CD4/CD8 ratio: [ratio]; Flow cytometry: abnormal T-cell population
Skin Histology
Shows band-like dermal infiltrate with minimal epidermotropism; Sézary cells with cerebriform nuclei present
Flow Cytometry
Aberrant T-cell population: CD3+, CD4+, CD7-, [other markers]; Clonal population: [percentage]%
Molecular Studies
T-cell receptor clonality: clonal in blood and skin; [Additional molecular findings]
Staging Assessment
Clinical stage: [III/IV]; TNM: T4N[0-3]M[0-1]B[1-2]
Prognostic Factors
Age: [years]; Tumor burden: [low/high]; LDH: [normal/elevated]; Performance status: [ECOG score]
Final Diagnosis
Sézary syndrome, WHO-EORTC classification