Sézary syndrome C84.1

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Hadrian Tran

Our authors

Last updated on: 29.10.2020

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Synonym(s)

Mycosis fungoides erythroderma stage; Reticulohistiocytosis cutanea hyperplastica benigna cum melanodermia; Reticulohistiocytosis cutanea hyperplastica maligna cum melanodermia; Sézary-Baccaredda Syndrome; Sezary Syndrome; T-cell erythroderma

History
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Sézary and Bouvrain, 1938

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

Etiopathogenesis
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The erythrodermal variant of Mycosis fungoides is being discussed. The circulating Sézary cells predominantly show a T-helper cell type (CD4+/Cd8+), more rarely variants like CD4-/CD8+ or CD4+/CD8-. They seem to have a Th2 reactivity which suppresses the Th1 reaction. This results in a general Th1/Th2 imbalance. Here, upregulation of GATA3, a key transcription factor in Th2 differentiation, in Sézary cells may play an important role, as does the expression of galectin-1 on these cells.

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

In contrast to Mycosis fungoides, Sézary cells express CD27 in increased amounts, and TWISTI is upregulated in Sézary cells, whereas it is not expressed in normal lymphocytes.

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

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

Localization
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Generalized.

Clinical features
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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).

Laboratory
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Leukaemic 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 molecularly (detection of a T cell clone by Southern blot or PCR, chromosomal alterations).

  • Blood count: leukocytosis, relative lymphocytosis, Lutzner cells (or Sézary cells) > 5% of total lymphocytes; absolute numbers: > 1000 cells/ml.
  • PCR: T-cell receptor gene rearrangement (diagnostically important but not conclusive; detection of monoclonality of the β or γ chain).
  • FACS analysis: CD2 pos., CD3 pos., CD4 pos., CD5 pos., CD27 pos., 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 patients
  • LDH elevation in 40% of patients
  • Increase in CD4/CD8 ratio in 20-25% of patients
  • TCR rearrangement in the skin in 89% of patients
  • TCR rearrangement in the blood in 84% of patients

Histology
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  • Monomorphic, subepidermal infiltrate of atypical lymphocytes with strongly lobed nucleus (Lutzner cells) and distinct epidermotropy. Abscess-like accumulation of tumor cells in the epithelium (Pautrier abscesses) is present but less frequent than in plaque-stage MF: blasts, eosinophilic granulocytes and atypical plasma cells are occasionally found. 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 the skin as well as in peripheral blood.
  • The cause for the "homing" into the skin is still unclear. In order to enter the skin, the T cells have to express certain "homing receptors". These include the cutaneous lymphocyte antigen (CLA), which is not expressed on normal ZH2 cells. CLA is a carbohydrate molecule that is bound to a nuclear protein with the involvement of a fucosyltransferase VII (fut7). Other homing specific factors are CCR4, CCR8, CCR10 and CXR3. Blocking these factors may lead to new therapeutic approaches.

Diagnosis
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The diagnosis is made clinically. According to studies and clinical experience, the diagnosis is made on average 12 months (min. 1 month; max. 8 years) after initial manifestation. In addition to the routine laboratory and organ analysis, the diagnosis is confirmed by histology with immunophenotyping, molecular biological methods such as determination of the T-cell receptor gene rearrangement and flow cytometry, lymph node diagnostics (sonographic examination of skin-near lymph nodes) and, if necessary, lymph node biopsy and fine tissue diagnostics or bone marrow biopsy. S.u. lymphoma, cutaneous T-cell lymphoma. The diagnostic and predictive value of bone marrow biopsy is questioned by various authors.

Differential diagnosis
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Clinical:

  • Erythrodermic psoriasis: psoriatic history; often pustules absent in Sezyry syndrome. No tumour cells in the peripheral blood.
  • Erythrodermic atopic eczema: usually combined with a long history of atopy; no alopecia; detection of specific IgE. No tumor cells in peripheral blood.
  • Pityriasis rubra pilaris: long disease career, possible familiarity; no tumor cells in peripheral blood.
  • Erythrodermic drug exanthema: sudden event; mostly exfoliative blistering

Histological:

  • Other T-cell lymphomas: in this difficult differential diagnosis the clinical findings must be taken into account.

Therapy
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Many retrospective studies on therapy do not include precise information on the diagnosis and stage of the disease, which makes it impossible to compare therapeutic options. We see the ranking of the listed therapeutic modalities in Sézary Syndrome largely in line with the S2k guideline (2016):

Therapy of the first choice:

  • Extracorporeal photopheresis (as monotherapy or in combination with other procedures). Monotherapeutic ECP ensured a survival time of 60 months in a patient group (n = 37) (in a historical control group: 30 months). Good treatment results were achieved in a group of 12 patients with a combination therapy of ECP, PUVA (3 times/week), IFN-alpha (3 times/week 3-9 million IU) and external glucocoids. Other combination partners with ECP that have been proven in individual studies are: GM-CSF (see below growth factors) and bexarotene.
  • PUVA therapy + interferon alfa-2a

Therapy of the 2nd choice:

  • HN2 (mechloroethamine; older American therapy recommendations, which have not been widely used in Europe so far)
  • Bexarotene (second-line therapy)
  • Chlorambucil/glucorticoids (Winkelmann scheme)
  • Low-dose methotrexate
  • Whole body irradiation with fast electrons (over a period of 12-16 weeks; GD 10-36Gy)
  • CHOP Scheme Polychemotherapy
  • Denileukin Diftitox (the preparation is not approved in Germany [ off-label use])
  • Alemtuzumab (MabCampath): genetically engineered, humanized IgG1 Kapa 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.
  • Doxyrubicin (pegylated liposomal doxorubicin cannot normally be prescribed by statutory health insurance companies), fludarabine, cladribine, gemcitabine
  • Allogeneic stem cell transplantation
  • Brentuximab Vedotin (off-label use)

Progression/forecast
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Average survival time of 3-5 years. 5-year survival time: < 30%.

Note(s)
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The coexistence of B-cell leukemia and Sézary syndrome have been described.

Literature
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  1. Baccaredda A (1937) Reticuloendotheliosi cutanea e melanodermia. Atti Soc ital Derm Sifilogr: 649-657
  2. Baccaredda A (1939) Reticulohistiocytosis cutanea hyperplastica cum melanodermia. Arch Derm Syph (Berlin) 179: 209-256
  3. Beylot-Barry M et al (2005) Is bone marrow biopsy necessary in patients with mycosis fungoides and Sézary syndrome? Br J Dermatol 152: 1378-1379
  4. Booken N et al (2010) The combination therapy with extracorporeal photopheresis, interferon-alpha, PUVA and local glucocorticoids in the treatment of Sézary syndrome. JDDG 8: 428-438
  5. Bunn PA et al (1994) Systemic therapy of cutaneous t-cell lymphomas (mycosis fungoides and the sezary syndrome). Ann Internal Med 121: 592-602
  6. Dummer R et al (2001) Current pathogenetic aspects of Sezary syndrome and mycosis fungoides dermatologist 52: 189-192
  7. Duvic M et al (2001) Phase 2 and 3 clinical trial of oraö bexarotene (Tagretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol 137: 581-593
  8. Fierro MT et al (2006) Expression pattern of chemokine receptors and chemokine release in inflammatory erythroderma and Sezary syndrome. Dermatology 213: 284-292
  9. Fung MA et al (2002) Practical evaluation and management of cutaneous lymphoma. J Am Acad Dermatol 46: 325-357
  10. Introcaso CE et al (2008) Total skin electron beam therapy may be associated with improvement of peripheral blood diease in Sezary syndrome. JAAD 58: 592-595
  11. Karsai S et al (2008) Sézary syndrome coexisting with B-cell chronic lymphocytic leukemia: case report. Dermatology 216: 68-75
  12. Macheiner W et al (2003) Sezary syndrome and seronegative polyarthritis: treatment with extracorporeal photochemotherapy. J Am Acad Dermatol 48: 220-226
  13. Nicolay JP et al (2016) Sézary syndrome: from unresolved questions to new therapeutic approaches. SDDG 14: 256-265
  14. Olsen et al (2001) Pivotal phase III trial of two dose levels of denileukin difitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncolog 19: 376-378
  15. RichardsonSK et al (2006) High clinical response rate with multimodality immunomodulatory therapy for Sezary-syndromes. Clin Lymphoma Myeloma 7: 226-232
  16. Scarisbrick JJ et al (1999) Secondary malignant neoplasms in 71 patients with Sezary syndrome. Arch Dermatol 135: 1381-1385
  17. Schappell DL et al (1995) Treatment of advanced mycosis fungoides and sezary syndrome with continuous infusions of methotrexate followed by fluorouracil and leucovorin rescue. Arch Dermatol 131: 307-313
  18. Sézary A, Bouvrain Y (1938) Érythrodermie avec présence de cellules monstrueuses dans le derme et le sang circulant. Bull Soc Franc Derm Syph 45: 254-260

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Last updated on: 29.10.2020