Sezary Syndrome

Sa A. Wang, MD

Key Facts

Terminology

Sézary syndrome (SS) is defined by triad of
- Pruritic erythroderma
- High number of Sézary cells in blood (> 1,000/µL )
- Lymphadenopathy, usually generalized

Clinical Issues

SS presents de novo in most patients
Can be preceded by mycosis fungoides (MF)
- Cases should be designated as “SS preceded by MF”
Skin: Intractable pruritus and generalized erythroderma with edema (≥ 80% of skin surface)
Extracutaneous sites of involvement
- Lymph nodes, lung, liver
- Spleen, central nervous system, other organs
- Bone marrow is relatively spared
Most treatments are palliative, not curative
Total skin electron beam radiation with nonmyeloablative allogeneic SCT may be curative
Poor survival: Median < 2.5 years

Microscopic Pathology

Sézary cells (cells with cerebriform nuclei) in peripheral blood
Skin changes are very similar to mycosis fungoides
Lymph nodes show partial or total effacement of normal architecture

Top Differential Diagnoses

Nonneoplastic causes of erythroderma
Adult T-cell leukemia/lymphoma (ATLL)
T-cell prolymphocytic leukemia
Leukemia cutis (especially monocytic leukemia)
Peripheral T-cell lymphoma, not otherwise specified

Skin of patient with Sézary syndrome shows erythroderma. The patient’s back and left arm are shown in this field.

Peripheral blood smear from a patient with Sézary syndrome shows many large Sézary cells with folded cerebriform nuclei and scant to moderate cytoplasm; they are larger than neutrophils.

TERMINOLOGY

Abbreviations

Sézary syndrome (SS)

Synonyms

Erythrodermic cutaneous T-cell lymphoma (E-CTCL)

Definitions

SS defined by triad of
- Pruritic erythroderma
- High number of Sézary cells in peripheral blood (> 1,000/µL ) with
  - Confirmed T-cell clonality or
  - Increased CD4:CD8 ratio > 10 or
  - T-cell immunophenotypic aberrancies demonstrated by flow cytometric immunophenotyping
- Lymphadenopathy, usually generalized

ETIOLOGY/PATHOGENESIS

Unknown

Genetics, infectious agents, or environmental exposures may play a role

CLINICAL ISSUES

Epidemiology

Incidence
- 5% of all cutaneous T-cell lymphomas
Age
- Adults; median: 60 years (range: 45-70 years)
Gender
- M:F = 1.5:1
Ethnicity
- Incidence in blacks 2x as high as in whites

Presentation

SS occurs de novo in most patients
Can be preceded by prodromal phase
- Pruritus or nonspecific dermatitis
Can be preceded by mycosis fungoides (MF)
- Patients must fulfill blood criteria for SS (T4B2)
- These cases should be designated as “SS preceded by MF”
  - Recommendation of International Society for Cutaneous Lymphomas (ISCL)
Skin: Intractable pruritus and generalized erythroderma with edema (≥ 80% of skin surface)
- Associated with alopecia, ectropion, leonine facies
- Nail dystrophy, plantar hyperkeratoses with extremely painful fissuring
- Secondary bacterial infection
- Some cases show marked photosensitivity
  - Mimic chronic actinic dermatitis
Extracutaneous involvement
- Lymph nodes
- Liver, lung, spleen, central nervous system, and any other organs
- Bone marrow is relatively spared
Increased prevalence of secondary malignancies, especially lymphoma
- May be attributable to decreased normal CD4(+) T cells
Hypereosinophilic syndrome has been reported to be associated with SS
- Can cause end organ dysfunction

Laboratory Tests

Work-up should include
- Complete blood count with differential
- Serum chemistry tests of liver and renal function, electrolytes, and lactate dehydrogenase (LDH)
- Serologic tests for viruses
  - HTLV-1, HIV, hepatitis B
Flow cytometric immunophenotyping of peripheral blood useful for
- Confirming clonality
- Detecting immunophenotypic aberrancies
Molecular analysis of T-cell receptor (TCR) genes for assessment of clonality
- T-cell clone can be seen in up to 20% of reactive skin conditions

Treatment

Most therapies are palliative and not curative
- Extracorporeal photoimmunotherapy
- Bexarotene (retinoid)
- Methotrexate
- Vorinostat (histone deacetylase inhibitor)
- Alemtuzumab (anti-CD52)
- Denileukin diftitox (anti-CD25 IL-2 diphtheria fusion protein)
- High-dose chemotherapy
  - Etoposide, vincristine, doxorubicin, bolus cyclophosphamide, oral prednisone (EPOCH)
- Autologous hematopoietic stem-cell transplantation following high-dose chemotherapy
  - Can produce remissions, but early relapses are common
Total skin electron beam radiation with nonmyeloablative allogeneic stem cell transplantation (SCT)
- Possibly curative approach

Prognosis

Poor; median survival < 2.5 years
- Predictors of poor prognosis
  - Advanced age
  - Elevated serum LDH

MICROSCOPIC PATHOLOGY

Histologic Features

Peripheral blood
- Cells with cerebriform nuclei (Sézary cells)
  - Can range in size from small to large
- Small Sézary cells (< 12 µm in diameter)
- Large Sézary cells (> 14 µm in diameter)
- Sézary cells are not completely specific
  - Especially small forms can be seen in reactive conditions
  - Most large cells are neoplastic
Skin
- Changes are very similar to MF
- In ˜ 2/3 patients with SS, skin biopsy shows diagnostic findings
- Epidermotropism is variable
  - Can be absent in some biopsy specimens
  - Atypical cells are present only in dermis; often perivascular
- Tumor cell size can be variable
  - Cell population is often monotonous (more so than MF)
- In ˜ 1/3 of patients, only nonspecific changes without abnormal lymphocytes
  - Cannot distinguish from nonneoplastic erythroderma using histologic criteria
Bone marrow
- Often not involved or only minimal involvement
- When involved, Sézary cell infiltrate is often sparse
  - Mainly interstitial pattern; often patchy

Cytologic Features

Cerebriform cells; can be small, medium, or large

Lymph Nodes

Involved lymph nodes show partial or total effacement of normal architecture by Sézary cells
- Dense, monotonous infiltrate of Sézary cells
- Capsular invasion or extranodal invasion is often present
- B-cell follicles may be reduced in number or small
Changes of dermatopathic lymphadenopathy are often present with
- Increased interdigitating dendritic and Langerhans cells
- Increased epithelioid venules and scattered melanophages

ANCILLARY TESTS

Immunohistochemistry

Pan-T-cell antigens(+), TCR-αβ(+)
- Loss or dim expression of T-cell antigens(+/-)
CD4(+), CD8(-)
CD25(-/+), CD30(-/+), CD52(+)
B-cell antigens(-)
Ki-67 moderate to high

Flow Cytometry

CD2(+), CD3(+), CD5(+), CD7(+), TCR-αβ(+)
CD4(+), CD8(-)
TdT(-), CD1a(-), CD10(-), B-cell antigens(-)
Immunophenotypic aberrancies are common; best detected by flow cytometry
- Increased CD4:CD8 ratio
- Loss of CD7, CD26, or other antigens
- Altered expression levels of CD2, CD3, CD4, or CD5
Vβ analysis is useful to confirm clonality and for quantifying neoplastic cells
- Can be used for initial diagnosis and monitoring treatment response