HAEM5:Sezary syndrome: Difference between revisions

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<ref name=":3" />. Pruritis is the most commonly reported symptom<ref name=":1" />. 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 <ref name=":0" />.  

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==Sites of Involvement==

Clonal T cell receptor gene (TCR) rearrangement is characteristic of SS.  Characteristically, ''PLS3'', ''DNM3'', ''TWIST1'', and ''EPHA4'' are overexpressed, and ''STAT4'' is underexpressed.

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<ref name=":2" />.  

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

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 <ref name=":0" />.  Death usually results from opportunistic infections, as SS patients are at an increased risk for infection due to underlying immune dysfunction<ref name=":1" />. 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 <ref name=":0" />.  

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==Individual Region Genomic Gain / Loss / LOH==

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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<ref name=":0" />.  

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<ref name=":2" />.  

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==Characteristic Chromosomal Patterns==

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Numerical and structural alterations are common in SS.  These include loss of 1p, 6q, and 10q with gains of 7 and 8q<ref name=":4">{{Cite journal|displayauthors=1|last=Almeida|first=Ana|date=December 2015|title=The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome|url=|journal=Nature Genetics|volume=47|pages=|via=}}</ref><ref name=":0" />.  Isochromosome 17q is a recurrent finding in SS<ref name=":0" />.  

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.<ref name=":4" />  

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==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<ref name=":4" />.

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<ref name=":3" />.

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==Epigenomic Alterations==

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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<ref name=":3" />.

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<ref name=":2" />.<br />

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==Genetic Diagnostic Testing Methods==