What is Sezary syndrome, a type of cutaneous T-cell lymphoma (CTCL)?

What is Sézary Syndrome?

Sézary syndrome is an aggressive leukemic variant of cutaneous T-cell lymphoma characterized by the triad of erythroderma (generalized red, scaly skin), generalized lymphadenopathy, and the presence of clonally related neoplastic T cells with cerebriform nuclei (Sézary cells) in the skin, lymph nodes, and peripheral blood. 1

Classification and Epidemiology

Sézary syndrome is classified as an aggressive cutaneous T-cell lymphoma (CTCL) with poor prognosis according to the WHO/EORTC classification system. 1

• CTCL represents approximately 70% of all primary cutaneous lymphomas, with mycosis fungoides and Sézary syndrome being the most common clinicopathological subtypes. 1
• The annual incidence is approximately 0.7 per 100,000 population in the U.K., with significantly higher male incidence (1.6:1.0 male-to-female ratio) and peak age between 50-74 years. 1
• Sézary syndrome is rare, representing approximately 14% of CTCL cases in prospective databases. 2

Diagnostic Criteria

Diagnosis requires demonstration of an identical clonal T-cell receptor gene rearrangement in both skin and peripheral blood, combined with at least one of the following blood criteria: 1

• Total Sézary cell count >1000 cells/μL, OR
• Expanded CD4 T-cell population with CD4:CD8 ratio ≥10, OR
• Expanded CD4+ T-cell population with abnormal immunophenotype including CD4+CD7- (>30%) or CD4+CD26- (>40%)

Key Diagnostic Features

• Erythroderma affecting ≥80% of body surface area with intense pruritus. 2, 3
• Circulating malignant T cells with cerebriform nuclei (Sézary cells) visible on peripheral blood smear. 1
• Generalized lymphadenopathy is characteristic. 1, 3
• Skin biopsy shows CD4+ epidermotropic infiltrate of T cells, though rare CD8+ variants occur. 1

Clinical Behavior and Prognosis

Sézary syndrome is a systemic disease (leukemia) by definition and carries an aggressive clinical course with poor prognosis. 1

• Median overall survival is 2-4 years, though recent therapeutic advances have improved outcomes. 4
• Five-year overall survival is approximately 50.7% in contemporary series from high-volume centers. 4
• Stage IVB disease (visceral organ involvement) carries a 5-year overall survival of 0-15% and disease-specific survival of 0%. 5, 6
• Older age (>65 years) and male sex are poor prognostic factors. 4

Important Clinical Pitfall

The erythrodermic rash can mimic common benign conditions like psoriasis, atopic dermatitis, or eczema, leading to delayed diagnosis when patients are treated empirically with topical steroids without biopsy. 7 Persistent rash unresponsive to standard therapy warrants early dermatology referral and skin biopsy.

Relationship to Mycosis Fungoides

Mycosis fungoides and Sézary syndrome are closely related both clinically and pathogenetically but are distinct entities. 1

• Mycosis fungoides typically presents with patches and plaques progressing over years, while Sézary syndrome presents with erythroderma and leukemic involvement from onset. 1
• Both share the same staging system (TNMB: tumor-node-metastasis-blood) to document disease extent. 5

Treatment Implications

Being a systemic disease by definition, systemic treatment is required for Sézary syndrome. 1

• Skin-directed therapies like PUVA or potent topical steroids may be used only as adjuvant therapy, not as primary treatment. 1
• Extracorporeal photopheresis (ECP), either alone or in combination with interferon-α, retinoids, or other modalities, has been suggested as first-line treatment, with overall response rates ranging from 30-80%. 1
• Complete responses are rare (approximately 8.3% in prospective series) and can be achieved through three methods: combined immunomodulatory therapy, targeted biologic agents (alemtuzumab, mogamulizumab), or allogeneic stem cell transplantation. 2
• Romidepsin (histone deacetylase inhibitor) is FDA-approved with objective response rates of 34-35% in clinical trials. 8

Critical Treatment Consideration

Immunosuppressive therapy should never be initiated based on clinical impression alone without excluding CTCL, as immunosuppression can worsen lymphoma and lead to aggressive disease progression. 9 Multiple skin biopsies, peripheral blood flow cytometry, T-cell receptor gene rearrangement studies, and imaging (PET-CT or CT chest/abdomen/pelvis) are mandatory before starting immunosuppression in erythroderma patients. 9