Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy

García-Díaz, Nuria; Piris, Miguel Á.; Ortiz‐Romero, Pablo L.; Vaqué, José P.

doi:10.3390/cancers13081931

Cited by 35 publications

(38 citation statements)

References 158 publications

(231 reference statements)

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“…Genetic aberration involving cell cycle and proliferation, chromosomal instability, and DNA repair have been observed in MF/SS [ 28 ]. Those genes are involved in different pathways such as epigenetic and/or chromatin regulation, TCR and T-cell/ cytokine signalling, Jak/signal transducer and activator of transcription (STAT), and phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt) and NF-kB pathway, configuring that a complex mutational landascape may be related to MF/SS pathogenesis [ 27 , 29 , 30 ]. Also microenvironment changes from early to advanced CTCL phases have been proposed in the pathogenesis of MF and SS.…”

Section: Introductionmentioning

confidence: 99%

TOX Expression in Mycosis Fungoides and Sezary Syndrome

et al. 2022

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Mycosis fungoides (MF) and Sezary syndrome (SS) are the two most common type of cutaneous T-cell lymphoma (CTCL). Currently, no markers can be clearly related to prognosis or to differential diagnosis between early stages and inflammatory benign diseases (IBD). The thymocyte selection-associated high mobility group box factor (TOX), has been proposed as a possible marker in differential diagnosis between early CTCL stages and IBD. Recently TOX has been related to prognosis. We aimed to investigate whether TOX may be a diagnostic or prognostic marker. MF and SS biopsies between 2010 and 2020 were retrieved. New tissues slides were stained with an anti-TOX antibody, (Clone NAN448B). On each slide, 5 fields were examined at high magnification (400×), to evaluate the percentage of marker-positivity in a quantitative way. Thirty-six patients (12 females and 24 males) and 48 biopsies were collected. Nine patients had multiple biopsies. TOX expression in MF/SS cases showed an increase from early to advanced phases. TOX was not regarded as a prognostic marker due to the absence of significant changes by comparing early MF cases with reactive conditions. TOX statistical significance increased in patients alive with disease and in those dead of disease (p = 0.013 and = 0.0005, respectively) as compared with patients in complete remission. Our results show that TOX should be regarded more as a prognostic than a diagnostic marker.

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Section: Introductionmentioning

confidence: 99%

TOX Expression in Mycosis Fungoides and Sezary Syndrome

et al. 2022

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“…Somatic GOF CARD11 mutations were initially described in ~10% of diffuse large B-cell lymphomas associated with constitutive NF-κB activity ( 21 ). Moreover, hypermorphic/GOF variants in CARD11 and other non-canonical NF-κB genes were also reported in patients with MF, Sézary Syndrome, and HTLV-1-driven adult T-cell lymphoma ( 20 , 22 , 23 ). More recently, somatic variants in CARD11 were found to be associated with solid tumors such as human sinonasal tumors ( 24 ).…”

Section: Discussionmentioning

confidence: 94%

“…Somatic CARD11 variants have been associated with several lymphoid malignancies ( 20 ). Somatic GOF CARD11 mutations were initially described in ~10% of diffuse large B-cell lymphomas associated with constitutive NF-κB activity ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

Hyper-IgE and Carcinoma in CADINS Disease

et al. 2022

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BackgroundAtopic dermatitis (AD) affects up to 25% of children and 10% of adults in Western countries. When severe or recurrent infections and exceedingly elevated serum IgE levels occur in AD patients, an inborn error of immunity (IEI) may be suspected. The International Union of Immunological Societies classification lists variants in different genes responsible for so-called Hyper-IgE syndromes. Diagnosing an underlying IEI may influence treatment strategies.MethodsClinical and diagnostic workup of family members are presented including a detailed immunological description and histology of the carcinoma. Functional testing of the novel variant in CARD11 underlying ‘CARD11-associated atopy with dominant interference of NF-kB signaling’ (CADINS) was performed.ResultsWe report on an 18-year-old patient with a long-standing history of infections, accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis. The working diagnosis of common variable immunodeficiency was revised when a novel heterozygous CARD11 variant [c.223C>T; p.(Arg75Trp)] was identified. Functional studies confirmed this variant to have a dominant negative (DN) effect, as previously described in patients with CADINS. Five other family members were affected by severe atopy associated with the above variant, but not hypogammaglobulinemia. Malignancies occurred in two generations: an HPV-positive squamous cell carcinoma and a cutaneous T-cell lymphoma. So far, one patient is under treatment with dupilumab, which has shown marked benefit in controlling severe eczema.ConclusionThe phenotypic spectrum associated with heterozygous CARD11 DN mutations is broad. Partial T-cell deficiency, diminished IFN-γ cytokine and increased IL-4 production, were identified as disease-causing mechanisms. Malignant disease associated with germline CARD11 DN variants has only been reported sporadically. HPV vaccination in teenage years, and cytology screening analogous with routine cervical swabs may be recommended. Treatment with dupilumab, a monoclonal antibody blocking interleukin-4- and interleukin-13 signaling, may be of benefit in controlling severe and extended AD for some patients as reported for STAT3 loss-of-function.

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“…To provide a new perspective compared with the latest reviews on molecular heterogeneity and deregulated pathways found in CTCLs [ 26 , 27 ], here we focused on comparison analyses performed between paired skin and blood samples of SS cells. Emerging data describe the molecular signals triggered in these two SS cell subpopulations.…”

Section: Introductionmentioning

confidence: 99%

Combined High-Throughput Approaches Reveal the Signals Driven by Skin and Blood Environments and Define the Tumor Heterogeneity in Sézary Syndrome

Cristofoletti

Bresin

Fioretti

et al. 2022

Cancers

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Sézary syndrome (SS) is an aggressive variant of cutaneous t-cell lymphoma characterized by the accumulation of neoplastic CD4+ lymphocytes—the SS cells—mainly in blood, lymph nodes, and skin. The tumor spread pattern of SS makes this lymphoma a unique model of disease that allows a concurrent blood and skin sampling for analysis. This review summarizes the recent studies highlighting the transcriptional programs triggered by the crosstalk between SS cells and blood–skin microenvironments. Emerging data proved that skin-derived SS cells show consistently higher activation/proliferation rates, mainly driven by T-cell receptor signaling with respect to matched blood SS cells that instead appear quiescent. Biochemical analyses also demonstrated an hyperactivation of PI3K/AKT/mTOR, a targetable pathway by multiple inhibitors currently in clinical trials, in skin SS cells compared with a paired blood counterpart. These results indicated that active and quiescent SS cells coexist in this lymphoma, and that they could be respectively treated with different therapeutics. Finally, this review underlines the more recent discoveries into the heterogeneity of circulating SS cells, highlighting a series of novel markers that could improve the diagnosis and that represent novel therapeutic targets (GPR15, PTPN13, KLRB1, and ITGB1) as well as new genetic markers (PD-1 and CD39) able to stratify SS patients for disease aggressiveness.

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Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy

Cited by 35 publications

References 158 publications

TOX Expression in Mycosis Fungoides and Sezary Syndrome

TOX Expression in Mycosis Fungoides and Sezary Syndrome

Hyper-IgE and Carcinoma in CADINS Disease

Combined High-Throughput Approaches Reveal the Signals Driven by Skin and Blood Environments and Define the Tumor Heterogeneity in Sézary Syndrome

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