Sézary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4 positive T cells. Here we performed whole-exome sequencing of tumor-normal sample pairs from 25 Sézary syndrome and 17 other CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sézary syndrome including highly prevalent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A and CDKN1B tumor suppressors. Mutation analysis identified a broad spectrum of somatic mutations in key genes involved in epigenetic regulation (TET2, CREBBP, MLL2, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including MAPK1, BRAF, CARD11 and PRKG1 mutations driving increased MAPK, NFκB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sézary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.

Cutaneous T-cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing T cell. In early-stage disease, lesions are limited to the skin, but in later-stage disease, the tumor cells can escape into the blood, the lymph nodes, and at times the visceral organs. To clarify the genomic basis of CTCL, we performed genomic analysis of 220 CTCLs. Our analyses identify 55 putative driver genes, including 17 genes not previously implicated in CTCL. These novel mutations are predicted to affect chromatin (, ,, ), immune surveillance (, ), MAPK signaling (, ), NF-κB signaling (, ), PI-3-kinase signaling (, ), RHOA/cytoskeleton remodeling (), RNA splicing (), T-cell receptor signaling (, ), and T-cell differentiation (). Our analyses identify recurrent mutations in 4 genes not previously identified in cancer. These include CK1α (encoded by ) (p.S27F; p.S27C), PTPRN2 (p.G526E), RARA (p.G303S), and RLTPR (p.Q575E). Last, we functionally validate and as putative oncogenes. encodes a recently described scaffolding protein in the T-cell receptor signaling pathway. We show that RLTPR (p.Q575E) increases binding of RLTPR to downstream components of the NF-κB signaling pathway, selectively upregulates the NF-κB pathway in activated T cells, and ultimately augments T-cell-receptor-dependent production of interleukin 2 by 34-fold. Collectively, our analysis provides novel insights into CTCL pathogenesis and elucidates the landscape of potentially targetable gene mutations.

This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.

A safety signal for ACEIs, ARBs, and TZs and BCC and SCC, as well as for TZs and MM, was detected. An increased awareness and education, especially for those who are at high risk for skin cancer, are warranted for patients and healthcare providers. Further exploration of such associations for these commonly used drug classes is warranted.

Background: Exogenous ochronosis presents as an acquired asymptomatic hyperpigmentation on photoexposed areas, predominantly over bony prominences, and is caused by the topical application of several skinlightening agents. Observations: We describe a 63-year-old Hispanic woman who developed exogenous ochronosis lesions on her face after using topical bleaching creams containing hydroquinone, 2% to 3%, and oxybenzone, 2%, for several years. Dermoscopy revealed irregular brown-gray globular, annular, and arciform structures that corresponded to focal deposition of ochronotic pigment on the dermis. These deposits correlated with multiple bananashaped nonrefractile structures seen using reflectance confocal microscopy. Histopathologic sections revealed the deposition of a banana-shaped, yellow to brown material in the papillary and middle dermis. Ultrastructural