General
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• Sézary syndrome (SS) is defined by the triad of erythroderma, generalized lymphadenopathy and the presence of clonally related neoplastic T cells with cerebriform nuclei (Sézary cells) in skin, lymph nodes and peripheral blood
• In addition, one or more of the following criteria are required: an absolute Sézary cell count of at least 1000/mm3, an expanded CD4+ T cell population resulting in a CD4/CD8 ratio of more than 10 and/or loss of one or more T cell antigens (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, Lyon 2008)

Epidemiology
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• Rare, <5% of all cutaneous T cell lymphomas
• Adults, usually men over 60

Etiology
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• Unknown, but a syndrome clinically indistinguishable is occasionally seen in HTLV-1 associated leukemia/lymphoma

Sites
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• By defition, a leukemia, therefore a generalized disease
• All visceral organs may be involved in the terminal stages
• Remarkable sparing of the bone marrow

Clinical features
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• Generalized exfoliative erythroderma, generalized lymphadenopathy and blood involvement by Sézary cells (resemble cells of mycosis fungoides)
• Pruritus, alopecia, ectropion, palmar/plantar hyperkeratosis, onychodystrophy, leonine facies (resembles a lion)
• Associated with monoclonal gammopathy and secondary neoplasms (carcinoma, other non-Hodgkin lymphomas), attributed to the loss of normal circulating CD4+ cells
• Skin lesions rarely become tumor masses

Case reports
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• 63 year old man with thrombotic microangiopathy (Nephrol Dial Transplant 2004;19:733)
• 66 year old man without erythroderma (Indian J Dermatol Venereol Leprol 2002;68:225)
• 74 year old man with coexisting CLL (Ann Biol Clin (Paris) 2003;61:94)
• 75 year old man with large cell transformation (Am J Clin Pathol 2000;113:792)

Treatment and prognosis
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• Poor prognosis; better with categories LN 0-2 or Dutch classification I-II with negative T cell rearrangement by PCR
• 10-20% 5-year survival rate; most die of opportunistic infections
• May transform to anaplastic large cell lymphoma with poor prognosis
• Staging: ISCL/EORTC Revision to the classification of mycosis fungoides and Sézary syndrome

Postulated normal counterpart
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• Mature epidermotropic skin homing CD4+ T cells

Clinical images
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Leonine facies

Erythroderma

Various images

Gross description
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• Erythroderma, generalized lymphadenopathy, rarely skin tumors

Micro description
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• Atypical lymphocytes (Sézary cells) are intermediate / large with basophilic cytoplasm, cerebriform nuclei, inconspicuous nucleoli; marrow usually normal, if involved the infiltrates are sparse and mainly interstitial
• May resemble mycosis fungoides in tissue, but more often monotonous infiltrates and sometimes no epidermotropism
• 1/3 of cases have non-specific histology of the skin biopsy
• Peripheral blood: Romanowsky stained smears show large cells with slight cytoplasm containing PAS+, perinuclear vacuoles and large, cerebriform, hyperchromatic nuclei

Micro images
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Skin, courtesy of Dr. Mark R. Wick

Flow cytometry images
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Various images

Positive stains
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• CD2, CD3, CD4 (most cases), CD5, TCRβ+, CLA, CCR4, CD45RO, P140, SCS

Negative stains
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• CD8 (most cases), CD7, CD26

Molecular and cytogenetics description
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• Clonal rearrangement of T cell receptor genes, but no specific chromosomal abnormalities
• Complex karyotypes including abnormalities of 1p, 6q, 10q, 17p, 19
• TP53 and p16 inactivation, JUNB amplification

Differential diagnosis
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• Chronic actinic reticuloid
• Drug-induced erythroderma
• Eczema and psoriasis for cases with non-specific histology

Additional references
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• WHO Classification of Skin Tumours, Lyon 2006, Am J Clin Pathol 2007;127:496, Am J Clin Pathol 2006;125:364, Blood 1996;88:2385

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