Sézary Syndrome

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

Madison E. Hannay, DO, Medical University of South Carolina

Tingting Barrett, MD, Medical University of South Carolina

Daynna J. Wolff, PhD, Medical University of South Carolina

Cancer Category/Type

Mature T-cell neoplasm / Cutaneous T-cell lymphoma

Cancer Sub-Classification / Subtype

Sézary syndrome

Definition / Description of Disease

Triad of erythroderma, generalized lymphadenopathy, and clonal neoplastic T lymphocytes with cerebriform nuclei (Sézary cells) in the skin, lymph nodes, and peripheral blood.

To diagnose Sézary syndrome (SS), one or more of the following criteria are required: an absolute Sézary cell count ≥ 1000/µL, an expanded CD4+ T-cell population resulting in a CD4:CD8 ratio of ≥10, and loss of one or more T-cell antigens.

Synonyms / Terminology

Sézary disease

Epidemiology / Prevalence

Rare; accounts for <5% of all cutaneous T-cell lymphomas.  SS characteristically occurs in adult patients aged >60 years and has a male predominance. The prevalence is approximately 0.3 cases per 100,000 people. Incidence is greater in black patients compared with white patients (roughly 50%). Childhood cases have also been reported.

Clinical Features

Erythroderma and generalized lymphadenopathy developing over weeks to months. Scaling is commonly found on the patch and plaque lesions. The lesions are usually located in areas infrequently exposed to sunlight. Pruritis is the most commonly reported symptom. Other features include alopecia, ectropion, palmar or plantar hyperkeratosis, and onychodystrophy.

An increased prevalence of secondary cutaneous and systemic malignancies has been reported in SS, likely a result of the hypogammaglobulinemia associated with the skewed T-cell ratio and loss of normal circulating CD4+ T-cells .  

Sites of Involvement

Skin, lymph nodes, and peripheral blood.  In advanced stages, SS can involve any visceral organ, most commonly the oropharynx, lungs, and CNS.  Bone marrow involvement is variable.

Morphologic Features

Histologic features in the skin overlap with mycosis fungoides (MF).  The atypical T-cell infiltrate in SS may be more monotonous with variable epidermotropism; up to one third of skin biopsies may only show nonspecific changes.

The lymph nodes involved by SS show architectural effacement with a dense population of monotonous (Sézary) cells.

Circulating atypical, cerebriform mononuclear (Sézary) cells are seen on examination of peripheral blood.

Immunophenotype

The clonal T lymphocytes (Sézary cells) are CD3+, CD4+, CD45(CLA)+ and CD8-.  They lack CD7 and CD26.  Almost all cases express PD1 (CD279), CCR4, and CCR7.

Peripheral blood flow cytometry shows a CD4+/CD7- (>30%) or CD4+/CD26- (>40%) T-cell population.

Finding	Marker
Positive (universal)	CD3, CD4, CD45 (CLA), PD1 (CD279), CCR4, CCR7
Positive (subset)
Negative (universal)	CD8, CD7, CD26
Negative (subset)

Chromosomal Rearrangements (Gene Fusions)

Clonal T cell receptor gene (TCR) rearrangement is characteristic of SS.  Characteristically, PLS3, DNM3, TWIST1, and EPHA4 are overexpressed, and STAT4 is underexpressed.

Balanced translocations have not been detected in SS.

Gene fusion between CTLA4 and CD28 is highly expressed. Additional fusion events include TYK2-UPF1, COL25A1-NFKB2, FASN-SGMS1, SMS1-ZEB1, SPATA21-RASA2, PITRM1-HK1, and BCR-NDUFAF6.

Characteristic Chromosomal Aberrations / Patterns

Numerical and structural alterations are common in SS.  These include loss of 1p, 6q, and 10q with gains of 7 and 8q.  Isochromosome 17q is a recurrent finding in SS.

Deletions are often associated with loss of tumor suppressor genes such as recurrent deletions involving 17p13.1 (TP53), 13q14.2 (RB1), 10q23.3 (PTEN) and 12p13.1 (CDKN1B). Focal chromosome 2p23.3 deletions (DNMT3A) were observed.

Genomic Gain/Loss/LOH

Recurrent gain-of-function mutations in SS include PLGC1, CD28, and TNFRSF1B. Recurrent loss-of-function mutations include ARID1A, which has been observed in 40% of SS cases.

Somatic duplications can be found ranging from duplications of chromosome bands (8p23.3-q24.3, 17p11.2-q23.2) to entire chromosomes (chr 18). Several somatic deletions have also been demonstrated including a 15-25 Mb deletion on 17p12-p13.3.

Gene Mutations (SNV/INDEL)

The mutational landscape of Sezary syndrome is complex and over 1000 different gene mutations have been identified. Mutational signature characterized by C>T substitutions at NpCpG trinucleotides and C>A substitutions at CpCpN trinucleotides and C>T substitutions at CpCpN and TpCpN trinulceotides have been identified.

RHOA mutations have also been described in SS.  Mutations (including single nucleotide mutations and copy number variants) in the JAK/STAT pathway likely result in the constitutive activation of STAT3 in Sézary cells.  Inactivating mutations in TP53 and deletions of CDKN2A (p16INK4a) are frequent.  Mutations in DNMT3A have been reported in SS.

Mutations in epigenetic regulator genes including TET2, CREBPP, KMT2C (MLL3) histone H3 lysine 4 (H3K4) methyltransferase, WI/SNF, and NuRD chromatin-remodeling complexes have been demonstrated as well.

Recurrent mutations in TP53, ITPR1, DSC1 and PKHD1L1 are found in a cohort study by Prasad et al. The study found damaging mutations to ITPR1 in two Sezary Syndrome patients. ITPR1 mediates calcium release from the endoplasmic reticulum and may be functional partners with BCL2, which is an apoptosis suppressor.

Mutations in the p53, p15, p16, JunB, and PTEN genes are generally found in late-stage disease, suggesting that they are secondary genetic events after disease initiation.

Epigenomics (Methylation)

Hypermethylation and inactivation of genes involved in the FAS-dependent apoptotic pathway is frequently reported in SS.

Genes and Main Pathways Involved

Loss of Fas expression, which is involved in T-cell apoptotic pathways, has also been reported. Specifically, changes affecting the Fas ligand is seen in 50-83% of cases. Loss of Fas expression is seen in 14-59% of cases.

Genes involved in NF-kB signaling, chromatin remodeling, and DNA damage response have also been found to be altered. Notably, alterations to signaling pathways including Jak/signal transducer and activator of transcription (STAT) signaling and cell-cycle checkpoint have been shown to be involved in the pathogenesis.

Diagnostic Testing Methods

As discussed in the morphology section, histologically, a band-like lymphocytic infiltrate are often seen in the upper dermis. Epidermotropism of atypical T cells with small to normal size with irregular (cerebriform) nuclei is frequent. Pautrier microabscesses consisting of malignant T cells and dendritic cells can be a specific but insensitive sign.

Immunohistochemical staining generally shows atypical CD4+ T cells, or sometimes CD8+ T cells in children with mycosis fungoides. Loss of T cell antigens (CD2, CD3, CD5, CD7, CD26) may be seen. Clonal T-cell receptor rearrangement may be detected via PCR.

Flow cytometry can be used to identify potentially malignant subsets of T-cells as well as for quantifying treatment response.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

SS is aggressive; however, prognosis is variable and largely depends on stage.  A median survival of 32 months and a 5-year survival rate of 10-30% has been reported .  Death usually results from opportunistic infections, as SS patients are at an increased risk for infection due to underlying immune dysfunction. Lymph node and visceral involvement are poor prognostic factors, as is the degree of peripheral blood involvement by Sézary cells.  Bone marrow involvement is of unknown prognostic relevance .  

Links

Mycosis Fungoides

References

1. Arber DA, et al., (2017). Sézary syndrome, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p390-391.

2. Prasad et al. Identification of Gene Mutations and Fusion Genes in Patients with Sezary Syndrome. Journal of Investigative Dermatology (2016), volume 136.

3. Hwang ST, Janik JE, Jaffe ES, Wilson WH, (2008). Mycosis fungoides and Sezary syndrome, in Lancet. Vol 371, March 15 2008.

4. Rook, AH and Olsen, EA. Clinical presentation, pathologic features, and Diagnosis of Sézary syndrome. UpToDate. Uptodate.com. Last updated: June 24, 2020. Date accessed: January 29, 2021.

5. Almeida et al. The mutational landscape of cutaneous T cell lymphoma and Sezary Syndrome. Nature genetics. Volume 47. Number 12. December 2015.

Notes

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