LT and SOX9 expression are associated with gene sets that distinguish Merkel cell polyomavirus (MCPyV)-positive and MCPyV-negative Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive malignant neuroendocrine tumour. There are two subsets of MCC, one related to Merkel cell polyomavirus (MCPyV) and the other to ultraviolet radiation (UVR). MCPyV-positive and MCPyV-negative MCCs have been considered to be different tumours, as the former harbour few DNA mutations and are not related to UVR, and the latter usually arise in sun-exposed areas and may be found in conjunction with other keratinocytic tumours, mostly squamous cell carcinomas. Two viral oncoproteins, large T antigen (LT; coded by MCPyV_gp3) and small T antigen (sT; coded by MCPyV_gp4), promote different carcinogenic pathways. OBJECTIVES: To determine which genes are differentially expressed in MCPyV-positive and MCPyV-negative MCC; to describe the mutational burden and the most frequently mutated genes in both MCC subtypes; and to identify the clinical and molecular factors that may be related to patient survival. METHODS: Ninety-two patients with a diagnosis of MCC were identified from the medical databases of participating centres. To study gene expression, a customized panel of 172 genes was developed. Gene expression profiling was performed with nCounter technology. For mutational studies, a customized panel of 26 genes was designed. Somatic single nucleotide variants (SNVs) were identified following the GATK Best Practices workflow for somatic mutations. RESULTS: The expression of LT enabled the series to be divided into two groups (LT positive, n = 55; LT negative, n = 37). Genes differentially expressed in LT-negative patients were related to epithelial differentiation, especially SOX9, or proliferation and the cell cycle (MYC, CDK6), among others. Congruently, LT displayed lower expression in SOX9-positive patients, and differentially expressed genes in SOX9-positive patients were related to epithelial/squamous differentiation. In LT-positive patients, the mean SNV frequency was 4.3; in LT-negative patients it was 10 (P = 0.03). On multivariate survival analysis, the expression of SNAI1 [hazard ratio (HR) 1.046, 95% confidence interval (CI) 1.007-1.086; P = 0.02] and CDK6 (HR 1.049, 95% CI 1.020-1.080; P = 0.001) were identified as risk factors. CONCLUSIONS: Tumours with weak LT expression tend to co-express genes related to squamous differentiation and the cell cycle, and to have a higher mutational burden. These findings are congruent with those of earlier studies.

Merkel cell carcinoma (MCC) is an aggressive form of skin tumour. There are two subtypes of MCC: one of them is related to a virus called Merkel cell polyomavirus (MCPyV); the other one is related to persistent exposure to sunlight. The aim of this research was to find differences between these subtypes in their molecular behaviour (the genes that are expressed and the mutations that may be found). To do this, we carried out two studies, one to investigate gene expression (the process cells use to convert the instructions in our DNA into a functional product such as a protein) and one to look at gene mutations (changes in the DNA sequence). We found that the tumours that were not related to MCPyV expressed genes related to epithelial differentiation (the process by which unspecialized cells gain features characteristics of epithelial cells, which, among other things, make up the outer surface of the body), which means that the origin of both MCC subtypes may be different. We also found that MCPyV-related tumours had fewer mutations. Our findings are important because they help us to understand the biology of the MCC subtypes and could help with the development of new treatments for people diagnosed with skin tumours.

Self-Healing Juvenile Cutaneous Mucinosis: A Report of Two Cases With Differing Evolution.

ABSTRACT: Self-healing juvenile cutaneous mucinosis is a rare entity, characterized by the presence of subcutaneous nodules together with frequent nonspecific systemic symptoms, which occurs in the pediatric age and characteristically resolves spontaneously. Although the diagnostic criteria do not require a biopsy to be performed, it is frequently performed, and an abundant dermal mucin deposition will be observed together with other features such as fibroblastic proliferation. Although the prognosis is benign, follow-up is required for the eventual development of a rheumatologic disease.We present 2 clinical cases, describing the clinical findings and their histopathologic correlation. Comparatively, the outcome in both cases was different: in one case, the mucinosis resolved without any related event in the follow-up, and in the other case, the resolution was accompanied by the subsequent development of idiopathic juvenile arthritis.

Influence of serum vitamin D level in the response of actinic keratosis to ingenol mebutate.

Vitamin D (VD) serum levels, and keratinocytic basal expression of vitamin D receptor (VDR) before treatment of actinic keratoses (AK) have been previously reported as possible biomarkers of the response of AK to treatments. We intended to evaluate the association between these and other serum and immunohistochemical parameters with the response of AK to treatment with topical ingenol mebutate (IM). Twenty-five patients with AK on the head were treated with topical IM 0.015% gel once daily for 3 days. Biopsies were taken at baseline and 6 weeks after treatment. Immunohistochemical staining was performed for VDR, P53, Ki67, Aurora B, Survivin and ß-catenin. Basal serum 25(OH)D levels were determined. IM was more effective for KIN I and II AKs than in KIN III, and histological responders showed significantly higher serum VD levels (30.278 [SD 8.839] ng/mL) than nonresponders (21.14 [SD 7.079] ng/mL, p = 0.023). In addition, mean basal expression of VDR (45.63 [SD 16.105] %) increased significantly (57.92 [SD 14.738] %, p = 0.003) after treatment with IM. A significant decrease after treatment in the expression of several markers of aggressiveness and progression to squamous cell carcinoma, namely P53, Ki-67, aurora B kinase and survivin, was also observed. Our results support a relationship between VD status and the response of AK to treatment with topical IM, suggesting that its previous correction to proper serum levels in VD-deficient patients could improve the response of AK to the treatment.

Sonography of subcutaneous nodules following immunization with histopathological correlation: a three-case series.

Subcutaneous nodules are a rare adverse event following immunization frequently associated with suboptimal injection procedures and aluminium-containing vaccines. We present three cases of subcutaneous nodules following immunization describing their clinical signs, histopathological features and ultrasound findings and demonstrating the use of sonography as an aid to the diagnosis of this entity.

Nódulo reumatoide benigno en sóleo. Reporte de un caso / Benign rheumatoid nodule in the soleus muscle. Case report

RESUMEN Los nódulos reumatoides benignos son nódulos subcutáneos, idénticos en su morfología e histología a los que ocurren en el transcurso de la artritis reumatoide (AR), que aparecen en personas sin síntomas de artritis y con factor reumatoide (FR) negativo. Se presenta el caso de un varón de 46 arios de raza caucasiana que consultó por tumoración en la pierna derecha. Destacaba negatividad de factor reumatoide, anticuerpos anti péptido citrulinado, anticuerpos antinucleares y anticuerpos anticitoplasma de neutrófilo, así como normalidad de los reactantes de fase aguda. Una ecografía musculoesquelética mostró una tumoración sólida de 3,5 x 1,5 cm, de márgenes bien definidos, en músculo sóleo, con una estructura heterogénea hipoecoica con vascularización intra y perilesional. La resonancia magnética evidenció una tumoración de carácter fibroso sin datos sugestivos de agresividad. Una biopsia guiada por ecografía mostró histología característica de nódulo reumatoide. Se discuten la clínica, el diagnóstico, el diagnóstico diferencial y el tratamiento de los nódulos reumatoides benignos.

ABSTRACT Benign rheumatoid nodules are subcutaneous nodules, identical in morphology and histo logy to those that occur in the course of rheumatoid arthritis. They appear in people without symptoms of arthritis and with negative rheumatoid factor. The case is presented of a 46-year-old Caucasian man who consulted for a tumour inthe right leg. He was negative for rheumatoid factor, anti-citrullinated protein antibodies, antinuclear antibodies, and antineutrophil cytoplasmic antibodies, as well as for acute phase reactants. A musculoskeletal ultrasound showed a solid tumour of 3.5 × 1.5 cm with well-defined margins in the soleus muscle, and with a heterogeneous hypoechoic structure with intra- and peri-lesional vascularisation. The magnetic resonance imaging showed a fibrous tumour with no signs suggestive of aggressive growth. An ultrasound-guided biopsy sho wed the characteristic histology of the rheumatoid nodule. The clinical picture, diagnosis, differential diagnosis, and treatment of benign rheumatoid nodules are discussed.