ARP-T1-associated Bazex-Dupré-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-Dupré-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.

CENPV Is a CYLD-Interacting Molecule Regulating Ciliary Acetylated α-Tubulin.

CYLD is a deubiquitylase with tumor suppressor functions, first identified in patients with familial cylindromatosis. Despite many molecular mechanisms in which a function of CYLD was reported, affected patients only develop skin appendage tumors, and their precise pathogenesis remains enigmatic. To elucidate how CYLD contributes to tumor formation, we aimed to identify molecular partners in keratinocytes. By using yeast two-hybrid, coprecipitation, and proximity ligation experiments, we identified CENPV as a CYLD-interacting partner. CENPV, a constituent of mitotic chromosomes associating with cytoplasmic microtubules, interacts with CYLD through the region between the third cytoskeleton-associated protein-glycine domain and the active site. CENPV is deubiquitylated by CYLD and localizes in interphase to primary cilia where it increases the ciliary levels of acetylated α-tubulin. CENPV is overexpressed in basal cell carcinoma. Our results support the notion that centromeric proteins have functions in 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.

Keratoacanthoma: a distinct entity?

Keratoacanthoma (KA) are common but exceptional benign tumors, often appearing on sun-exposed areas of light skinned people and showing spontaneous resolution. The goal of this study was to review existing literature, to point out the etiological complexity of KA biology and to answer the controversial debate if or not KA is a distinct entity or a variant of squamous cell carcinoma (SCC). Relying on recent results, we highlight that KA is an individual lesion with a unique molecular signature caused by alterations in the TGFß signalling pathway. These recent findings will help to understand the nature of KA and to develop new reliable diagnostic tools, simplifying the discrimination of the histologically similar KA and SCC.

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.

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.

Psoriasis, anti-tumor necrosis factor therapy, and tuberculosis: report of three challenging cases and literature review.

INTRODUCTION: The era of biologic therapies has provided new options for the treatment of chronic plaque psoriasis. However, safety concerns have led to intensive screening and monitoring of patients receiving anti-tumor necrosis factor alpha (anti-TNF-alpha) agents. METHODS: The authors describe the cases of three patients with moderate to severe psoriasis treated with anti-TNF agents, with challenging diagnostic and treatment aspects regarding tuberculosis (TB) infection, a serious adverse event associated with this type of treatment. The cases are discussed in the context of a comprehensive literature review describing the risk of TB associated with the use of TNF inhibitors. A critical review of the clinical trials that have tested the safety of these agents is also presented. RESULTS: One patient, who tested negatively for latent TB infection (LTBI) during screening, developed active TB under adalimumab therapy. For two other patients the diagnosis and management of LTBI in relation to anti-TNF therapy represented a challenge. Although clinical trials involving the use of anti-TNF therapy for psoriasis haven't demonstrated a high TB incidence, active TB is continuously reported in association with this treatment. CONCLUSIONS: Findings from clinical practice and the scientific literature indicate that anti-TNF therapies are associated with an increased risk of TB, and close monitoring of patients is needed.

Tuberculosis infection versus anti-tumor necrosis factor therapy: screening challenges in psoriatic patients.

OBJECTIVES: The aim of this study was to analyze the performance of the tuberculin skin test (TST) for screening and monitoring patients treated with anti-tumor necrosis factor agents, in a high-incidence area. METHODS: A 3-year retrospective study was carried out on 268 subjects. The study included 68 patients with moderate-to-severe psoriasis, screened for latent tuberculosis infection (LTBI) and subjects without psoriasis (100 adults and 100 children) with close contact with infected individuals. RESULTS: Positive tuberculin skin test (TST) results (induration >5 mm) were observed in 70.5% (48/68) of patients with psoriasis, higher than those observed in subjects with suspicion of tuberculosis or with close contact with infected individuals: 51% (51/100) in the adult group and 30% (30/100) in the children group. CONCLUSIONS: These results show that the prevalence of LTBI evaluated with the TST in the psoriatic group is higher than in subjects without psoriasis. LIMITATION: The positive reactions were not confirmed by other verification methods.

Multiple disseminated glomuvenous malformations: do we know enough?

Multiple glomuvenous malformations (GVMs), also known as glomangiomas, are uncommon entities with histological features of both glomus cells proliferation and venous malformation. A 14-year-old boy was admitted to our clinic with multiple dermal blue nodules, disseminated in different segments of the body. The patient's family history was positive for similar lesions; his mother and maternal grandmother had some asymptomatic blue nodules on their body. Histological examination showed a tumor composed of multiple caveronous vessels surrounded by glomus cells, positive for alpha smooth muscle actin, HHF35 (pan-actin), and h-caldesmon. This is a case of multiple GVMs, a rare disease caused by mutations in glomulin gene, with an autosomal dominant pattern of inheritance. The clinical and histopathological features are briefly discussed.