Lymphoma & related disorders

Mature T/NK cell disorders

T/NK cell disorders with a leukemic component

Sézary syndrome



Topic Completed: 14 May 2021

Minor changes: 14 October 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: Sézary syndrome [title] pathology review[ptyp]


Mario L. Marques-Piubelli, M.D.
Roberto N. Miranda, M.D.
Page views in 2020: 4,369
Page views in 2021 to date: 4,795
Cite this page: Marques-Piubelli ML, Torres-Cabala CA, Miranda RN. Sézary syndrome. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBsezary.html. Accessed October 24th, 2021.
Definition / general
Essential features
Terminology
  • Erythrodermic CTCL includes all primary cutaneous lymphoma that evolve to erythroderma, such as Sézary syndrome (SS) and erythrodermic mycosis fungoides
  • SS was first described by Albert Sézary in 1938 (Lancet 2008;371:945, Eur J Cancer 2017;77:57)
ICD coding
  • ICD-O: 9701/3 - Sézary syndrome
  • ICD-10: C84.1 - Sézary disease
Pathophysiology / etiology
  • Mycosis fungoides and SS are thought to arise from chronic antigenic stimulation; early mycosis fungoides lesions show increased numbers of dendritic cells and upregulation of their antigen presenting cell (APC) ligands B7 and CD40 and their respective T cell costimulatory ligands CD28 and CD40L (J Am Acad Dermatol 2014;70:205.e1)
  • Both mycosis fungoides and SS have as cell of origin the skin resident CD45RO+ effector memory T cell (Lancet 2008;371:945)
  • Antigen presenting dendritic cells could maintain the survival and proliferation of clonal T cells: higher specific human leukocyte antigen (HLA) class II alleles than the general population (Lancet 2008;371:945)
  • Skin microbiomes (e.g. as Chlamydia spp) could play a role in the pathogenesis by the stimulation of clonality in T cells but it is still controversial (Lancet 2008;371:945)
  • Abnormalities in pathways: NFκB / JAK STAT activation, cell cycle dysregulation / apoptosis and DNA structural dysregulation affecting gene expression (Nat Genet 2015;47:1465)
  • Micro RNA expression profile detected differences between erythrodermic mycosis fungoides and SS (Acta Derm Venereol 2019;99:1148)
  • Chemokines receptors (Lancet 2008;371:945, Curr Hematol Malig Rep 2016;11:468, J Am Acad Dermatol 2011;64:352)
    • CCR4 and CCR10 play a role in the homing of malignant T cells to skin where they bind to ligands on endothelial cells, keratinocytes or Langerhans cells
      • CCL17 is a major CCR4 ligand and it is increased in the serum of patients with mycosis fungoides and SS
      • May explain the lower epidermotropism observed in SS compared with mycosis fungoides
    • Loss of CD26 promotes the inactivation of CXCL12, which is the CXCR4 ligand
  • T helper 2 (Th2) response is characteristic of SS as well as that of tumor stage mycosis fungoides; overexpression of CD47 in Sézary cells is under the influence of Th2 cytokines, such as IL-4, IL-7 and IL-13 (Blood Adv 2019;3:1145, Curr Hematol Malig Rep 2016;11:468, J Am Acad Dermatol 2011;64:352)
Clinical features
  • Erythroderma is the key feature for diagnosis and is defined by involvement of > 80% of body surface and may range from mild to intense (J Am Acad Dermatol 2012;67:1189, Lancet 2008;371:945, Eur J Cancer 2018;93:47, Curr Hematol Malig Rep 2016;11:468)
    • Alopecia and plaques at initial clinical presentation are uncommon (systemic symptoms usually absent)
    • Nail dystrophy, blepharoconjunctivitis and ectropium can be present in advanced disease
    • Palms and sole usually show thickening, scales and fissures
    • Median duration of all dermatologic symptoms before diagnosis: 3.5 years
      • Erythroderma is present usually 1.7 years before diagnosis
    • Clinical presentation with erythroderma with < 1 x 109/L is defined as pre-Sézary and some patients progress to SS, while others follow a more indolent clinical course
  • Pruritus is often present (Lancet 2008;371:945)
  • Systemic symptoms usually absent (J Am Acad Dermatol 2012;67:1189)
  • Adenopathy is usually present (J Am Acad Dermatol 2012;67:1189)
  • Bone marrow involvement in approximately 20% of the cases (J Am Acad Dermatol 2012;67:1189)
  • Cases may be preceded by mycosis fungoides and should be designated as SS preceded by mycosis fungoides; these cases are different from de novo SS (Am J Hematol 2019;94:1027)
Diagnosis
  • Characterized by the presence of erythroderma, generalized lymphadenopathy and clonal T cells (same clone in skin, lymph node and peripheral blood) in addition to 1 or more of the following criteria (Am J Hematol 2019;94:1027, Eur J Cancer 2018;93:47, Am J Clin Pathol 2011;136:944, Curr Hematol Malig Rep 2016;11:468, J Am Acad Dermatol 2011;64:352):
    • Absolute Sézary cell count ≥ 1 x 109/L (manual count or by flow cytometry)
    • Alternative diagnostic criteria: ≥ 40% of CD4+ / CD7- and ≥ 30% of CD4+ / CD26- T cells (flow cytometry)
      • TRBC1 is more sensitive and specific for detection of clonal T cells by flow cytometry
  • Expanded CD4+ T cell population with CD4:CD8 ≥ 10
    • It is reliant on the absolute CD8 count and the ratio may decrease after treatment
  • Loss of one or more T cell antigens
  • Demonstration of T cell clonality by southern blot or PCR based methods
  • Use of V beta antibodies allows quantification of the clone (obsolete)
    • Clonality by flow cytometry: constant chain of T cell receptor: TRBC1 (Int J Mol Sci 2021;22:1817)
    • Use of high throughput sequencing is more sensitive but not widely used
  • Cytogenetic demonstration of an abnormal clone
  • Bone marrow involvement is not a defined criteria for SS
  • Criteria for blood response (see staging table below):
    • Complete response (CR): B2 should change to B0
    • Partial response (PR): at least 50% reduction of tumor burden
    • Progressive disease (PD): B0 or B1 to B2 with an increase in absolute counts of ≥ 50% or B2 with an increase in absolute counts of ≥ 50% or loss of response with an increase in absolute counts ≥ 1x109/L and ≥ 50% from nadir
    • Relapse: increase in absolute counts of ≥ 1x109/L in the context of CR
Staging / staging classifications
  • Staging of mycosis fungoides and SS is performed according to the International Society for Cutaneous Lymphomas (ISCL) and the European Organization for Research and Treatment of Cancer (EORTC) (Eur J Cancer 2017;77:57, Blood 2016;127:3142)

Skin
T1 Limited patches, papules or plaques covering < 10% of the skin surface:
T1a: patch only
T1b: plaque with or without patch
T2 Patches, papules or plaques covering ≥ 10% of the skin surface:
T2a: patch only
T2b: plaque with or without patch
T3 One or more tumors (≥ 1cm diameter)
T4 Confluence of erythema covering ≥ 80% body surface area
Node
N0 No clinically abnormal peripheral lymph node
N1 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0-2
N1a: clone negative
N1b: clone positive
N2 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3
N2a: clone negative
N2b: clone positive
N3 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 3 - 4 or NCI LN4; clone positive or negative
Nx Clinically abnormal peripheral lymph nodes with no histological confirmation
Visceral
M0 No visceral organ involvement
M1 Visceral involvement (must have pathological confirmation)
Peripheral Blood (PB)
B0 Absence of significant blood involvement: ≤ 5% Sézary cells in PB
B0a: clone negative
B0b: clone positive
B1 Low blood tumor burden: > 5% Sézary cells in PB and does not meet criteria of B2
B1a: clone negative
B1b: clone positive
B2 High blood tumor burden: ≥ 1000/µL Sézary cells in PB with clone positive

  • SS is defined as stage IVA1 (T1-T4, N0-N2, M0, B2) and above
Prognostic factors
Case reports
Treatment
Clinical images

Contributed by Roberto N. Miranda, M.D.
Prominent exfoliative lesion

Prominent exfoliative lesion

Prominent erythroderma

Prominent erythroderma

Gross images

Contributed by Roberto N. Miranda, M.D.
Central nervous system (CNS) involvement

Central nervous system (CNS) involvement

Microscopic (histologic) description
  • SS is histologically similar to mycosis fungoides but sometimes epidermotropism is not present (Lancet 2008;371:945, Curr Hematol Malig Rep 2016;11:468, J Am Acad Dermatol 2011;64:352)
    • May range from limited to superficial perivascular lymphocytic and eosinophilic dermatitis with or without spongiosis (atopic-like lesions) to lichenoid lymphocytic infiltrate
    • Pautrier microabscesses are not common
  • Peripheral blood (Lancet 2008;371:945)
    • Sézary cells: atypical lymphocytes of intermediate to large size and cerebriform nuclei
      • Similar cells, albeit few or rare may be found in healthy individuals or in patients with other inflammatory skin diseases
  • Lymph node (Am J Hematol 2019;94:1027, Cancer 1986;57:237)
    • Complete effacement of the nodal architecture by monotonous infiltrating population of Sézary cells
    • Large cell or blastoid morphology may occur in advanced stages.
Microscopic (histologic) images

Contributed by Roberto N. Miranda, M.D.
Cerebriform lymphocytes in peripheral blood smear

Cerebriform lymphocytes in peripheral blood smear

Bone marrow involvement

Bone marrow involvement

CD3 positivity

CD3 positivity

Epidermotropic and lichenoid lymphoid infiltrate

Epidermotropic and lichenoid lymphoid infiltrate

Epidermotropic infiltrate

Epidermotropic infiltrate


Cerebriform cytology

Cerebriform cytology

Lymph node touch print

Lymph node touch print

Lymph node involvement

Lymph node involvement

Cytological atypia Cytological atypia

Cytological atypia

Positive stains
Negative stains
Flow cytometry images

Contributed by Roberto N. Miranda, M.D.
Flow cytometry in SS

Flow cytometry in SS

Molecular / cytogenetics description
Sample pathology report
  • Skin, shave biopsy of the arm:
    • Primary cutaneous T cell lymphoma, most consistent with Sézary syndrome (see comment)
    • Comment: Section shows an adequate skin shave biopsy with mild spongiosis and perivascular and lichenoid infiltrate in superficial dermis with mild epidermotropism. The infiltrate is composed of small lymphocytes, with irregular nuclear contours (cerebriform-like), hyperchromatic nuclei and scant cytoplasm. Immunohistochemical studies show that the abnormal lymphocytes are diffusely positive for CD3, CD4, CD5 and CD45RO and negative for CD2, CD7 and CD30. The concurrent complete blood count (CBC) reveals lymphocytosis (7 x 109/L) with abnormal Sézary cell count and the flow cytometry immunophenotype of the peripheral blood revealed CD4+ lymphocytosis (5 x 109/L) with low CD8+ count (0.8 x 109/L) and expanded CD4+ CD26- (63%) and CD4+ CD7- (58%). According to clinical notes, the patient is a 67 year old man who presented to the department of dermatology with a 1 month history of generalized erythroderma (90% of skin involvement) and inguinal and axillary bilateral lymphadenopathy. In summary, patient presented with erythroderma and skin is involved by cerebriform T lymphocytes with minimal epidermotropism. Peripheral blood is involved morphologically by cerebriform lymphocytes that by flow cytometry express CD3, CD4 and lack CD7 and CD26. These features support the diagnosis of Sézary syndrome.
Differential diagnosis
Board review style question #1

Which of the following is true about Sézary syndrome (SS) shown above?

  1. Erythroderma is essential for the diagnosis
  2. Frequently presents as an indolent disease with favorable prognosis
  3. Lymph node involvement is uncommon
  4. Most common dermatologic lesion is plaque
Board review style answer #1
A. Erythroderma is essential for the diagnosis

Comment Here

Reference: Sézary syndrome
Board review style question #2
What is a consistent feature for the diagnostic criteria of Sézary syndrome (SS)?

  1. Absolute Sézary cell count ≥ 1 x 109/L
  2. Different T cell clones in skin, blood or lymph node
  3. Expanded CD8+ T cells with CD8:CD4 ≥ 10
  4. Loss of CD3 (T cell marker) expression
Board review style answer #2
A. Absolute Sézary cell count ≥ 1 x 109/L

Comment Here

Reference: Sézary syndrome
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