Postoperative Pyoderma Gangrenosum in Association with Renal Cell Carcinoma and Chronic Lymphocytic Leukemia

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare sterile neutrophilic dermatosis characterized by painful recurrent ulcerations. It is frequently associated with inflammatory bowel disease, rheumatoid arthritis, or malignancies. PG is a diagnosis of exclusion, and it is based on clinical presentation, histology, history of an underlying disease, and exclusion of other causes of ulceration. CASE REPORT: The authors report a 62-year-old male who developed a nonhealing ulcer at the site of incision following nephrectomy for renal cell carcinoma. Past medical history included chronic lymphocytic leukemia treated with rituximab. Histology of the skin lesion showed a phlegmonous nonspecific inflammation without being able to differentiate between a necrotizing wound infection and PG. The patient’s condition was initially diagnosed as an infectious process and treated accordingly. After unsuccessful results with systemic antibiotics, high-dose corticosteroids induced prompt healing of the wound. On these bases, the diagnosis of postoperative PG within chronic lymphocytic leukemia and renal cell carcinoma was made. CONCLUSION: Faced with postoperative necrotizing ulceration resistant to correctly administered antibiotics, PG must be considered. In such condition, the diagnosis must not be guided primarily by histology and early advice of a dermatologist is recommended

Molecular mechanisms in skin cancer

Les principaux types de cancer de la peau sont représentés par le carcinome basocellulaire (BCC), le carcinome squamocellulaire (SCC) et le mélanome. Le BCC apparaît comme une tumeur sporadique, mais les conditions génétiques complexes telles que les syndromes de Gorlin et de Bazex Dupré Christol (BDCS) sont également associés au développement de BCCs multiples. Le gène responsable, muté dans le syndrome de Gorlin, est PTCH1, un acteur clé de la voie Sonic Hedgehog (SHH), qui nécessite des cils primaires pour la transduction du signal. Le syndrome de Bazex a été récemment lié à des mutations du gène ACTRT1, codant la protéine ARP-T1. La cylindromatose familiale est une prédisposition génétique pour les tumeurs bénignes des appendices cutanés, causées par des mutations inactivantes du gène CYLD. En utilisant la technique de double hybride pour trouver les interacteurs de CYLD, nous avions précédemment montré que CYLD interagit avec TRAF-interacting protein (TRAIP). La même technique a permis d'isoler un autre ligand potentiel, la protéine centromérique V (CENPV). Le but de cette thèse est d'étudier si TRAIP est impliqué dans la pathogenèse du mélanome, le rôle du CENPV dans l'homéostasie épidermique et l'implication de l'ARP-Tl dans la formation des cils. L'expression de TRAIP a été significativement augmentée dans les lignées cellulaires de mélanome et les biopsies de mélanome primaires ou métastatiques. La suppression de l'expression de TRAIP dans des cellules de mélanome a conduit à une réduction significative de leur prolifération, suggérant un rôle dans la croissance du mélanome. Dans le deuxième projet nous avons démontré l'interaction CENPV/CYLD dans les cellules de mammifères et que CENPV pourrait être déubiquitiné par CYLD. En plus, nous avons construit une protéine de fusion de CENPV et mCherry qui a été localisée sur les cils primaires et qui a régulé les niveaux ciliaires de la tubuline acétylée. CENPV participe à l'homéostasie cutanée en régulant la prolifération des kératinocytes. De plus, le CENPV a été surexprimé en BCC, et sa suppression a suggéré divers rôles dans la prolifération et la régulation de la voie SHH par BCC. Un projet en cours a identifié ARP-T1 comme un interacteur de plusieurs protéines impliquées dans la ciliogenèse. En utilisant des cellules épithéliales pigmentées rétiniennes, nous avons trouvé qu'ARP-Tl se localise à la base ciliaire et régule la longueur ciliaire. Enfin, nous avons identifié un phénotype ciliaire dans le BCC associé au BDCS. Summary SUMMARY The major types of skin cancer are represented by basai cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. BCC usually appears as a sporadic tumor, but complex genetic conditions such as Gorlin and BCDS associate the development of multiple BCCs. The responsible gene mutated in Gorlin syndrome is PTCH1, a key player of the sonic hedgehog (SHH) pathway. SHH requires primary cilia for signal transduction. BCDS has been recently linked to mutations in ACTRT1 gene, encoding the ARP-T1 protein. Familial cylindromatosis is a genetic prédisposition for benign tumors of skin appendages, caused by inactivating mutations in CYLD gene. By using yeast two- hybrid screens for CYLD interactors, we have previously showed that CYLD interacts with the TRAF-interacting protein (TRAIP). The same screen isolated another potential ligand, which was found later to be identical with the centromeric protein V (CENPV). The aim of this thesis is to investigate whether TRAIP is implicated in melanoma pathogenesis, the rôle of CENPV in epidermal homeostasis and the involvement of ARP-T1 in cilia formation. TRAIP expression was significantly increased in melanoma cell lines and primary or metastatic melanoma biopsies. Suppression of TRAIP expression in melanoma cells was leading to a significant réduction in prolifération, suggesting a rôle in melanoma growth. In the second project, we demonstrated the CENPV/CYLD interaction in mammalian cells and that CENPV could be deubiquitinated by CYLD. Moreover, we constructed a CENPV-mCherry fusion protein, which localised to primary cilia and regulated the ciliary levels of acetylated tubulin. CENPV is involved in skin homeostasis by regulating keratinocytes prolifération. Moreover, CENPV was overexpressed in BCC, and knockdown experiments suggested rôles in BCC prolifération and régulation of SHH pathway. Finally, we identified ARP-T1 as an interactor of several proteins involved in ciliogenesis. Using retinal pigmented epithelial cells, which become ciliated upon differentiation, we found that ARP-T1 localizes at the ciliary base and regulates the ciliary length. Moreover, we identified a ciliary phenotype in BCC associated with BCDS

DNA copy number imbalances in primary cutaneous lymphomas (PCL)

Cutaneous lymphomas (CL) represent a clinically defined group of extranodal non-Hodgkin lymphomas harboring heterogeneous and incompletely delineated molecular aberrations. Over the past decades, molecular studies have identified several chromosomal aberrations, but the interpretation of individual genomic studies can be challenging.We conducted a meta-analysis to delineate genomic alterations for different types of PCL. Searches of PubMed and ISI Web of Knowledge for the years 1996 to 2016 identified 32 publications reporting the investigation of PCL for genome-wide copy number alterations, by means of comparative genomic hybridization techniques and whole genome and exome sequencing. For 449 samples from 22 publications, copy number variation data was accessible for sample based meta-analysis. Summary profiles for genomic imbalances, generated from case-specific data, identified complex genomic imbalances, which could discriminate between different subtypes of CL and promise a more accurate classification. The collected data presented in this study are publicly available through the “Progenetix” online repository

Biopsying parapsoriasis: quo vadis? Are morphological stains enough or are ancillary tests needed?

BACKGROUND: Parapsoriasis represents a group of cutaneous disorders that shows variable clinical aspects somehow resembling to psoriasis, how is reflecting by its name. It was first named by Brocq, in 1902, as an entity with three components: pityriasis lichenoides, small plaque parapsoriasis and large plaque parapsoriasis. Nowadays, under the name of parapsoriasis are included only the last two categories, that are considered disorders characterized by the presence of a mononuclear infiltrate in the dermis, composed of T-cells. Until now, there were not established pathognomonic histopathological features to diagnose parapsoriasis. AIM: The aim of the study was to investigate the epidemiological and morphological data of parapsoriasis cases diagnosed at Emergency City Hospital, Timisoara, Romania for a period of 12 years. MATERIALS AND METHODS: The study had two parts; one was retrospective and another one prospective. For the retrospective part, we searched 210111 patient files recorded in our Pathology Service for a period of 11 years, from January 2002 to December 2012. The slides were searched from the archive and re-read by two individual pathologists. For prospective part of the study, we reviewed 11815 histological slides read between January and June 2013. After inspection of the recorded files, the pathologists noted, were available, the localization and number of the lesions, together with symptoms. The biopsied specimens were initially processed with routine histological technique, the archive slides being stained with Hematoxylin and Eosin. While reading the slides, the pathologists paid attention to the architecture of the epidermis, the presence of epidermotropism and interface dermatitis, type of the dermal infiltrate and its distributions. CONCLUSIONS: In the present study, we emphasized the histopathological aspects of parapsoriasis in order to create a basic line that could help in the establishment of a uniformly accepted definition of parapsoriasis on histopathological grounds

ARP-T1-associated Bazex-Dupre-Christol syndrome is an inherited basal cell cancer with ciliary defects characteristic of ciliopathies

Actin-Related Protein-Testis1 (ARP-T1)/ACTRT1 gene mutations cause the Bazex-Dupre-Christol Syndrome (BDCS) characterized by follicular atrophoderma, hypotrichosis, and basal cell cancer. Here, we report an ARP-T1 interactome (PXD016557) that includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation. In agreement, ARP-T1 localizes to the midbody during cytokinesis and the basal body of primary cilia in interphase. Tissue samples from ARP-T1-associated BDCS patients have reduced ciliary length. The severity of the shortened cilia significantly correlates with the ARP-T1 levels, which was further validated by ACTRT1 knockdown in culture cells. Thus, we propose that ARP-T1 participates in the regulation of cilia length and that ARP-T1-associated BDCS is a case of skin cancer with ciliopathy characteristics. Park et al. characterise the interactome, localisation and function of Actin-Related Protein-Testis1 protein (ARP-T1), encoded by the ACTRT1 gene, associated with inherited basal cell cancer. They find that ARP-T1 is localised to the primary cilia basal body in epidermal cells, interacts with the cilia machinery, and is needed for proper ciliogenesis

Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas

Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupré-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1