Sézary syndrome C84.1

Rare, aggressive, erythrodermic (erythroderma > 80% of skin surface) and leukemic (> 1000 circulating tumor cells/µl in peripheral blood; clonal T-cell receptor rearrangement, increased CD4/CD8 ratio, and loss of CD7) cutaneous T-cell lymphoma (CTCL) with generalized lymphadenopathy and diffuse leukemic infiltrates in skin and possibly bone marrow. High recurrence rates as well as an unfavorable prognosis complicate its clinical course.

The erythrodermic variant of mycosis fungoides is discussed. However, the association is controversial.

The circulating Sézary cells, predominantly have a T helper cell type (CD4+/Cd8+), with variants such as CD4-/CD8+ or CD4+/CD8- being less common. They appear to have a Th2 reactivity that suppresses the Th1 response. This creates a general Th1/Th2 imbalance. It is possible that upregulation of GATA3, a key transcriptional factor in Th2 differentiation, plays a significant role in Sézary cells; as does expression of galectin-1 on these cells.

Recent studies suggest that Sézary cells are derived from mature T cells, e.g., regulatory Tcells (Treg cells), or Th2 and Th17 cells. It is unclear at which stage of maturation and by which mechanism the cells are arrested.

In contrast to mycosis fungoides, Sézary cells express more CD27. Furthermore, TWISTI is upregulated in Sézary cells, whereas it is not expressed in normal lymphocytes.

Furthermore, CD158k is considered a reliable diagnostic marker; CD158k functions as a co-inhibitory receptor on Sezary cells. The receptor CD158k recognizes CpG oligonucleotides (CpG-ODN), is activated by them and induces apoptosis via STAT3 .

Predominantly occurring in the 5th-7th decade of life. Men are affected more frequently than women.

Initially large erythema, which is not very characteristic, scaly and massively itchy. Rapid development of erythroderma ( Homme rouge) with leathery infiltrated, brown-red ( melanoerythroderma) skin with a tendency to diffuse hyperpigmentation, sometimes also diffuse weeping skin. Hyperkeratoses on palmae and plantae (47% of patients), diffuse alopecia (13%), onychodystrophy, pruritus. Obligatory are generalized, clearly enlarged, skin-near lymph nodes (unspecific lymphadenopathy in early stages of the disease, later in a high percentage of specific infestation). Bone marrow infestation (15%). Plaque-like and tumorous skin infiltrates may occur. Clinically characteristic are sharply defined areas of healthy skin in an erythrodermic environment ( nappes claires).

Characteristic are leukemic blood picture changes, which can be summarized morphologically (detection of Sézary cells in the blood smear or in the buffy coat by electron microscopy), immunophenotypically (CD4/CD8 ratio > 10 or CD4+/CD7- T cells > 40%) or molecular biologically (detection of a T cell clone by Southern blot or PCR, chromosomal alterations).

• Blood count: Leukocytosis, relative lymphocytosis, detection of large lymphocytic cells (Lutzner cells - or Sézary cells) > 5% of total lymphocytes; absolute counts: > 1000 cells/ml. PCR: T cell receptor gene rearrangement (diagnostically important but not confirmatory; evidence of β or γ chain monoclonality). FACS analysis: CD2 pos, CD3 pos, CD4 pos, CD5 pos, CD27pos, CD45 pos, RO pos. CD27 is discussed as a specific marker for Sézary cells.
• Polyclonal hypergammaglobulinemia in 25% of pat.
• Monoclonal hypergammaglobulinemia in 29% of pat.
• LDH elevation in 40% of pat.
• Increase in CD4/CD8 ratio in 20-25% of pat.
• TCR rearrangement in skin in 89% of pat.
• TCR rearrangement in blood in 84% of patients.

• Monomorphic, subepidermal infiltrate of atypical lymphocytes with highly lobulated nuclei (Lutzner cells) and marked epidermotropy. Abscess-like accumulation of tumor cells in the epithelium (Pautrier abscesses) are present but rarer than in MF at the plaque stage: occasional blasts are detectable as well as eosinophilic granulocytes and atypical plasma cells. Epidermis: Irregular acanthosis, focal parakeratosis, spongiosis.
• Immunohistology: Tumor cells express a T helper cell type (CD3+; CD4+; CD45R0+: 80% of cases); CD7 neg. Large blasts are reactive for CD30.
• Clonality of the T-cell population can be detected in skin as well as peripheral blood.
• The reason for "homing" into the skin is still unclear. In order to homing into the skin, T cells must express certain "homing receptors". These include cutaneous lymphocyte antigen (CLA), which is not expressed on normal ZH2 cells. CLA is a carbohydrate molecule that binds to a nuclear protein with the involvement of a fucosyltransferase VII (fut7). Other homing-specific factors include CCR4, CCR8, CCR10, and CXR3. Blockade of these factors may provide new therapeutic approaches.

Clinical:

• Erythrodermic psoriasis: psoriatic history; frequent pustular formations absent in Sézary syndrome. No tumor cells in peripheral blood.
• Erythrodermic atopic dermatitis: usually combined with a history of atopy for many years; no alopecia; evidence of spec. IgE. No tumor cells in peripheral blood.
• Pityriasis rubra pilaris: long-standing disease career, possible familiality; no tumor cells in peripheral blood.
• Erythrodermic drug eruption: sudden event; usually exfoliative blistering.

Histologic:

• Other T-cell lymphomas: clinical findings must be included in this difficult differential diagnosis.

Many retrospective studies on therapy do not include precise information on the diagnosis and staging of the disease, which makes a comparison of therapeutic options impossible. We consider the ranking of the listed therapeutic modalities in Sézary syndrome according largely to the S2 guideline (2021):

First-line therapy:

• Extracorporeal photopheresis (as monotherapy or in combination with other procedures). Monotherapeutic ECP ensured a survival of 60 months in one group of patients (n = 37) (in a historical control group: 30 months). Good treatment results were achieved in a group of 12 pat. with combination therapy of ECP, PUVA (3 times/week), IFN-alpha (3 times/week 3-9 million IU) and external glucocoticoids. Other combination partners with ECP proven in single studies are: GM-CSF (see below growth factors) and bexarotene.
• PUVA therapy + interferon alfa-2a
• Addendum: Interferon-alpha (Roferon®) has now been withdrawn from the market and is no longer available for treatment. Generic versions of the drug are not available. There are some case reports in the literature of successful treatment with available off-label pegylated interferons(PEG-IFN).

2nd-line therapy:

• Mogamulizumab (Poteligeo
  )is the first approved anti-CCR4 monoclonal antibody for targeted therapy of systemically pretreated adults with mycosis fungoides and Sézary syndrome. In the pivotal study, mogamulizumab showed a significant prolongation of progression-free survival compared to treatment with vorinostat, and the overall response rate was also more than fivefold higher.

• Bexarotene (second-line therapy)
• Low-dose methotrexate
• Chlorambucil/glucorticoids (Winkelmann regimen).
• Whole-body irradiation with fast electrons (over a 12-16 week period; GD 10-36Gy).
• Denileukin Diftitox (the drug is not approved in Germany [ off-label use])
• Alemtuzumab (MabCampath): genetically engineered, humanized IgG1 kappa monoclonal antibody that specifically binds to the 21- to 28-kDa glycoprotein CD52 (expressed by B and T cells) on the cell surface of lymphocytes.
• Doxorubicin (pegylated liposomal doxorubicin is not usually covered by the statutory health insurance), fludarabine, cladribine, gemcitabine.
• Allogeneic stem cell transplantation
• Brentuximab vedotin (off-label use)

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