Sézary Syndrome

Sézary syndrome is an aggressive variant of cutaneous T-cell lymphoma that presents with an erythrodermic rash, and is characterized by a malignant T-cell clone in the skin and peripheral blood. Diagnosis depends on skin biopsy with lab testing to confirm clonality in blood is consistent with clonality in skin. Staging, prognosis, treatment decisions, and monitoring are largely based on clinical evaluation of skin, blood, visceral organ, and lymph node involvement.

Diagnosis

Indications for Testing

Red, intensely itchy rash over much or most of the body, especially in individual ≥60 years

Laboratory Testing

  • Diagnosis is dependent on skin biopsy with dermatopathological review and immunohistochemical staining (see Histopathology); the following laboratory testing is also indicated
    • Assessment of clonality – essential testing per National Comprehensive Cancer Network (NCCN, 2018)
      • Polymerase chain reaction (PCR) screen
      • Flow cytometry T-cell receptor (TCR) V-beta clonality studies
      • Other methods include fluorescent in situ hybridization (FISH), karyotyping, or genome analysis
        • Clone found in blood should match that in skin
    • Flow cytometry – may be helpful
      • Detect and quantify phenotypically abnormal T-cell population
        • Should include CD3, CD4, CD7, CD8, and CD26 to assess for expanded CD4+ cells with increased CD4/CD8 ratio or with abnormal immunophenotype, including loss of CD7 or CD26) (NCCN, 2018)
        • Increased CD4/CD8 ratio >10; test is able to detect small T-cell neoplastic populations
      • Recommended over morphologic examination of peripheral blood smear, which is relatively insensitive due to morphological overlap with benign cells
    • Other testing
      • Complete metabolic profile (CMP) – characterization of visceral organ involvement
      • Lactate dehydrogenase (LDH) – assists with prognosis
      • Human T-cell lymphotropic virus (HTLV)
        • Evaluate at-risk population using serology or other method

Histopathology

  • Skin biopsy may show no diagnostic features – multiple biopsies recommended (NCCN, 2018)
    • Slides should be reviewed by hematopathologist or dermatopathologist experienced with cutaneous lymphomas
  • Immunohistochemical analysis of skin biopsy – essential to establish diagnosis
    • May demonstrate selective loss of pan-T-cell antigens, particularly in CD3, CD7, and CD8
    • Panel should include CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD25, CD30, CD56, TIA1, and granzymes B, βF-1, and TCR C gamma M1 antibody (NCCN, 2018)
  • Lymph node biopsy – suspicious lymph nodes should be biopsied if no skin diagnosis
  • Bone marrow biopsy – helpful in selected cases, but not essential

Differential Diagnosis

  • Malignant skin disease
  • Benign skin disease
    • Lymphomatoid drug reaction
    • Eczema/atopic or contact dermatitis
    • Psoriasis
    • Folliculitis
    • Pityriasis lichenoides et varioliformis acuta or chronica
    • Pigmented purpuric dermatoses
    • Graft versus host
    • Pityriasis rubra pilaris​
    • Hypereosinophilic syndrome
    • Scabies​/other arthropod bites
    • Viral infections
    • Lymphomatoid papulosis

Monitoring

  • There is no current consensus on response criteria, but such criteria have been proposed based on clinical end points (Olsen, International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer, 2011; NCCN, 2018)
  • Neoplastic mature T-cell testing (eg, by flow cytometry) can be used to monitor treatment response and follow disease levels in peripheral blood specimens for most patients with Sézary syndrome

Background

Epidemiology

  • Incidence – <0.1/100,000 (Teras, 2016)
  • Age – median onset, 60 years
  • Sex – M>F, 2:1
  • Ethnicity – occurs more frequently in African Americans

Classification

  • WHO classification of mature T- and NK-lymphoid neoplasms  (Swerdlow, 2016)
    • T-cell prolymphocytic leukemia
    • T-cell large granular lymphocytic leukemia
    • Chronic lymphoproliferative disorder of NK cells (provisional entity)
    • Aggressive NK-cell leukemia
    • Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorder of childhood
    • Hydroa vacciniformelike lymphoproliferative disorder
    • Adult T-cell leukemia/lymphoma (ATLL)
    • Extranodal NK/T-cell lymphoma, nasal type
    • Enteropathy-associated T-cell lymphoma
    • Monomorphic epitheliotropic intestinal T-cell lymphoma
    • Indolent T-cell lymphoproliferative disorder of the gastrointestinal (GI) tract (provisional entity)
    • Hepatosplenic T-cell lymphoma
    • Subcutaneous panniculitis-like T-cell lymphoma
    • Mycosis fungoides
    • Sézary syndrome
    • Primary cutaneous CD30-positive T-cell lymphoproliferative disorders
      • Lymphomatoid papulosis
      • Primary cutaneous anaplastic large cell lymphoma
    • Primary cutaneous gamma-delta T-cell lymphoma
    • Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (provisional entity)
    • Primary cutaneous acral CD8-positive T-cell lymphoma (provisional entity)
    • Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder (provisional entity)
    • Peripheral T-cell lymphoma, not otherwise specified (NOS)
    • Angioimmunoblastic T-cell lymphoma
    • Follicular T-cell lymphoma (provisional entity)
    • Nodal peripheral T-cell lymphoma with TFH phenotype (provisional entity)
    • Anaplastic large cell lymphoma (ALCL), ALK positive
    • ALCL, ALK negative
    • Breast implant-associated anaplastic large cell lymphoma (provisional entity)

Pathophysiology

  • Considered to be caused by malignant T-helper cells in dynamic equilibrium between the skin and vascular compartments
  • Sézary cells are abnormal lymphocytes that undergo nuclear, but not cytoplasmic, division
    • Benign cells that morphologically resemble Sézary cells can be seen in small numbers in normal peripheral blood

Clinical Presentation

  • Erythroderma, pruritus, with or without generalized adenopathy
  • Other symptoms include alopecia, edema, and thickening of the palms and soles
  • Most commonly, signs and symptoms arise de novo but can follow nonspecific dermatitis or mycosis fungoides
  • Patients diagnosed with Sézary syndrome generally have more advanced disease stage and worse prognosis than those diagnosed with classic mycosis fungoides localized to skin
  • Increased risk for second malignancies – most commonly, Hodgkin and non-Hodgkin lymphomas and myeloma (NCI PDQ, 2017)

ARUP Lab Tests

Aid in evaluation of hematopoietic neoplasms (ie, leukemia, lymphoma)

Monitor response to therapy in patients with established diagnosis of hematopoietic neoplasms

Markers selected based on provided clinical history and/or previous test results

Available markers:

T cell: CD1a, CD2, CD3, CD4, CD5, CD7, CD8, TCR γ-δ, cytoplasmic CD3

B cell: CD10, CD19, CD20, CD22, CD23, CD103, CD200, kappa, lambda, cytoplasmic kappa, cytoplasmic lambda

Myeloid/monocyte: CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase

Miscellaneous: CD11c, CD16, CD25, CD30, CD34, CD38, CD41, CD42b, CD45, CD56, CD57, CD61, HLA-DR, glycophorin, TdT, bcl-2, ALK-1, CD123, CD138, CD26, CD45, CRLF-2

Aid in the diagnosis of T-cell lymphoproliferative disorders

Aid in histologic diagnosis of Sézary syndrome

Stained and returned to client pathologist for interpretation; consultation available if needed

Related Tests

Assess visceral organ involvement

Assist with prognosis

Manual differential may detect Sézary cell changes in order to rule out leukemic cell disorders

Use to detect Sézary cells

  

Medical Experts

Contributor

Agarwal

Archana Mishra Agarwal, MD
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Hematopathology and Special Genetics, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®