Sézary syndrome

What is Sézary syndrome?

Sézary syndrome is an erythrodermic form of cutaneous T-Cell lymphoma (CTCL), a term that collectively includes all cutaneous lymphomas arising from T lymphocytes. The syndrome is named after Albert Sézary, a French dermatologist born in 1880. It is also called Sezary syndrome.

T lymphocytes are circulating immune cells that mature in the thymus. In Sézary syndrome, malignant T lymphocytes in the peripheral blood clonally match malignant T cells found in the skin.

Who gets Sézary syndrome?

Sézary syndrome is a disease of older adults. Epidemiological data is not available in New Zealand. Worldwide, incidence appears to be 0.8–0.9 per million with a male to female ratio of 2:1. It is not an inherited disease.

What causes Sézary syndrome?

The cause of Sézary syndrome remains largely unclear. The malignant T cells in the skin and blood have the following characteristics:

• CD4 positive: this indicates they are central memory T cells
• A significant percentage exhibit loss of CD26 and CD7
• Abnormal clonal Th2 cells
• Reduced Th1 (T-helper) cells

This contributes to endogenous immunosuppression.

How does Sézary syndrome present?

Skin signs

Patients with Sézary syndrome present with diffusely red, thickened and scaly skin. Pruritus (itch) is common, often severe, and can be difficult to manage. Other features may include:

• Slowly-developing generalised induration (firmness of the skin)
• Lichenification (increased skin markings due to scratching and rubbing)
• Scaly papules due to follicular prominence
• Thickened nails
• Ectropion (drooping of lower eyelid)
• Diffuse or patchy alopecia (hair loss)

These symptoms often lead to lack of sleep, anxiety and depression.

Very rarely, Sézary syndrome has been reported to present with pruritus, Sézary cells on biopsy of normal-looking skin, and no visible rash.

Sézary syndrome

Sézary syndrome

Sézary syndrome

Sézary syndrome

Systemic involvement

Other features of Sézary syndrome include:

• Peripheral lymphadenopathy: often generalised, involving neck, axillae, groins
• Enlarged spleen
• Less commonly, liver, lungs and gastrointestinal tract can be affected.

The following malignancies are associated with Sézary syndrome:

• Hodgkin lymphoma or non-Hodgkin lymphoma
• Melanoma
• Bladder cancer

How is Sézary syndrome diagnosed?

Sézary syndrome should be considered in any erythrodermic patient. Diagnosis requires clinicopathological correlation.

Skin biopsy

If possible, select an area of indurated skin for biopsy. Multiple biopsies are useful especially if morphology varies.

Features on light microscopy may include:

• Atypical lymphocytes infiltrating dermis
• Epidermotropism (cells migrating to epidermis)
• Lymphocytes with a single cerebriform nucleus (not diagnostic)
• Pautrier microabscesses, or intra-epidermal aggregates of atypical cells
• Immunohistochemistry stains positive for CD3+ and CD4+ cells

Blood tests

Sézary cells are large atypical mononuclear cells with a large cerebriform nuclei. They are found in large numbers in the peripheral blood of patients with Sézary syndrome. Smaller numbers may be found in healthy patients or those with other diseases.

Flow cytometry can demonstrate CD4+CD7- and CD4+CD26- T cells, which are characteristic of Sézary syndrome. T-cell antigens may also be absent (CD2, CD3, CD4 and/or CD5). The CD4:CD8 ratio is > 10, but is not diagnostic.

Lymph node biopsy

Excisional biopsies are required to distinguish between dermatopathic lymph node changes and reactive lymph node changes.

T-cell receptor (TCR) gene rearrangement tests

T-cell receptor (TCR) gene rearrangement tests may be performed on the skin specimen, circulating blood and lymph nodes. This test evaluates clonality of the cells, which should be similar in the 3 sites.

Differential diagnosis of Sézary syndrome

Other diagnoses considered in an erythrodermic patient may include:

• Mycosis fungoides (another form of CTCL)
• Psoriasis
• Pityriasis rubra pilaris
• Atopic dermatitis
• Other forms of dermatitis
• Drug eruption
• Idiopathic erythroderma
• Graft versus Host Disease (GVHD)

How is Sézary syndrome treated?

Treatment for Sézary syndrome is determined by the stage of disease and comorbidities.

TNMB criteria for staging CTCL are skin (T), lymph node (N), visceral involvement (M), blood (B). Sézary syndrome is classified as at least T4B2 (T4 erythroderma and B2 peripheral blood involvement). Classification also depends on lymph node or internal organ involvement:

• Stage IVA1: no internal organ involvement. Lymph nodes may be uninvolved or enlarged but with only minor histological abnormalities
• Stage IVA2: histologically abnormal lymph node involvement without internal organ involvement
• Stage IVB: internal organ involvement with or without lymph node involvement

There is no standard therapy for Sézary syndrome. Patients are prescribed topical and systemic medications. They may also receive UVB or PUVA phototherapy, and/or radiotherapy (localised superficial rays or total skin electron beam therapy).

Topical therapy for Sézary syndrome

Examples of topical therapy used to treat Sézary syndrome include:

• Emollients
• Topical corticosteroids
• Topical nitrogen mustard
• Potassium permanganate or dilute bleach baths to prevent infection

Extracorporeal photopheresis (ECP)

ECP is an immune-sparing therapy in which a photosensitizing agent (psoralen/8-methoxsalen) is combined with UVA to treat peripheral bloodwhich is extracted, irradiated and returned to the patient. It is the preferred first line therapy in early stages.

• Side effects include headache, fatigue, itch and transient hypotension (low blood pressure) with possible syncope (collapse).
• Response rates are improved when combined with biological response modifiers.
• ECP is currently not available in New Zealand but is available in Australia.

Biological response modifiers

Biologics are preferably used in conjunction with photopheresis. However, they can be used as part of single or multi-agent regimes if ECP is not available. They include:

• Denileukin diftitox (Ontak®), a protein combining Interleukin-2 and Diphtheria toxin approved in the treatment of cutaneous T-cell lymphoma that have the high affinity component of the IL-2 receptor
• Alemtuzumab (Campath-1H) is a monoclonal antibody directed against the lymphocytic antigen CD52 expressed on B- and T-cells. It has been used successfully off-label in Sezary syndrome.
• Other biologics are under investigation in this disease.

Other medications used in Sézary syndrome

Medications are often used in combination.

• Conventional "sedating" antihistamines to reduce the impact of pruritus
• Interferons: interferon alpha and gamma
• Retinoids: oral bexarotene, acitretin, isotretinoin
• Low dose methotrexate
• Histone deacetylase inhibitors: oral vorinostat or intravenous romidepsin

Chemotherapy for Sézary syndrome

Examples of chemotherapy agents used for Sézary syndrome are:

• Pegylated liposomal doxorubicin
• Gemcitabine
• Fludarabine
• Cladribine
• Pentostatin

What is the prognosis of Sézary syndrome?

Sézary syndrome is usually aggressive and prognosis is generally poor with a median survival between 2–4 years. Patients may respond transiently but relapse is often inevitable. The occasional patient has gone into remission after treatment.

Patients usually succumb to opportunistic infections due to immune suppression.