The Circulating Transcriptome as a Source of Biomarkers for Melanoma.

The circulating transcriptome is a valuable source of cancer biomarkers, which, with the exception of microRNAs (miRNAs), remains relatively unexplored. To elucidate which RNAs are present in plasma from melanoma patients and which could be used to distinguish cancer patients from healthy individuals, we used next generation sequencing (NGS), and validation was carried out by qPCR and/or ddPCR. We identified 442 different microRNAs in samples, eleven of which were differentially expressed (p < 0.05). Levels of miR-134-5p and miR-320a-3p were significantly down-regulated (p < 0.001) in melanoma samples (n = 96) compared to healthy controls (n = 28). Differentially expressed protein-encoding mRNA 5'-fragments were enriched for the angiopoietin, p21-activated kinase (PAK), and EIF2 pathways. Levels of ATM1, AMFR, SOS1, and CD109 gene fragments were up-regulated (p < 0.001) in melanoma samples (n = 144) compared to healthy controls (n = 41) (AUC = 0.825). Over 40% of mapped reads were YRNAs, a class of non-coding RNAs that to date has been little explored. Expression levels of RNY3P1, RNY4P1, and RNY4P25 were significantly higher in patients with stage 0 disease than either healthy controls or more advanced stage disease (p < 0.001). In conclusion, we have identified a number of novel RNA biomarkers, which, most importantly, we validated in multi-center retrospective and prospective cohorts, suggesting potential diagnostic use of these RNA species.

Does Schwann cell dedifferentiation originate dermal neurofibromas?

Dermal neurofibromas are characteristic of neurofibromatosis type one (NF1), and their developmental origin still unsolved. Although NF1 loss is required for neurofibroma initiation, some features of these benign tumors resemble a skin injury state and cutaneous trauma or other insults might support tumor development. Since adult terminal Schwann cells ensheathing nerve endings are able to dedifferentiate into a progenitor-like state in response to nerve crushing, we hypothesized that dedifferentiation of NF1-/- Schwann cells could be at the origin of human dermal neurofibromas. In support of this, here we show that CDH19 (a marker specific of Schwann cell precursors) and Schwann cell dedifferentiation marker SOX2 are significantly upregulated in NF1 tumors. We posit that onset of nerve regeneration might have a role in dermal neurofibroma initiation via dedifferentiation of NF1-/- Schwann cells.

Facial lesions in frontal fibrosing alopecia (FFA): Clinicopathological features in a series of 12 cases.

BACKGROUND: Facial lesions in frontal fibrosing alopecia (FFA) have been poorly described in published series. OBJECTIVE: We sought to describe facial lesions in FFA. METHODS: We reviewed our series of 55 cases of FFA, selecting 12 cases with clinically significant facial lesions. We performed a histologic study of these lesions. RESULTS: In addition to the observations already described in the literature such as facial papules or follicular red dots, we observed perifollicular and diffuse erythema, sometimes with a reticular pattern, and the gradual appearance of pigmented macules on facial skin. Biopsy specimens from the areas with facial erythema showed perifollicular and interfollicular lymphocytic infiltrate and fibrosis around vellus hair follicles. Histologic evaluation of pigmented macules sometimes exhibited an increased epidermal pigmentation and on occasions, pigmentary incontinence. LIMITATIONS: More patients are needed to determine the prevalence of these lesions in FFA. CONCLUSION: On facial skin of patients with FFA, we can observe papules or perifollicular erythema secondary to vellus hair follicle involvement. We describe diffuse erythema, owing to follicular and interfollicular lichenoid infiltrate, and the gradual appearance of pigmented macules, which could be secondary to an increased epidermal pigmentation or to pigmentary incontinence.

Association between EGFR gene polymorphisms, skin rash and response to anti-EGFR therapy in metastatic colorectal cancer patients.

Cetuximab and panitumumab are epidermal growth factor receptor (EGFR) inhibitors used in metastatic colorectal cancer (mCRC). Most patients develop a papulopustular rash that may predict tumor response to treatment. EGFR gene polymorphisms may also determine tumor response and appearance of skin rash. We hypothesized an association between EGFR gene polymorphisms, papulopustular rash and response to anticancer treatment. Four EGFR polymorphisms (-216, -191, CA-SSR, R521K) were analysed in 51 patients with mCRC receiving anti-EGFR. Severity of cutaneous rash and tumor response was measured following standard scales. We report an association between SNP-216 and tumor response (P = 0.003): no tumor progression occurred in TT genotype. Moreover, 92.3% of the responder patients developed skin rash, 62.9% of them presenting a grade ≥2 (P = 0.015). Thus, although underpowered, our preliminary data suggest that SNP-216 polymorphism of the EGFR gene could be useful in predicting tumor response and the appearance of severe skin rash might also be associated.

Epithelial to mesenchymal transition markers are associated with an increased metastatic risk in primary cutaneous squamous cell carcinomas but are attenuated in lymph node metastases.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in humans and approximately 5% metastasize, usually to regional lymph nodes. Epithelial to mesenchymal transition (EMT) is a process involving loss of intercellular adhesion, acquisition of a mesenchymal phenotype and enhanced migratory potential; epithelial markers, such as E-cadherin, are down-regulated and mesenchymal proteins (Vimentin), increased. OBJECTIVE: To investigate the expression of EMT markers in metastatic SCC (MSCC) and their corresponding metastases, and to correlate them with clinico-pathological factors associated with an increased risk of metastasis. METHODS: We performed a retrospective study that included 146 cSCC samples (51 primary non-metastatic, 56 primary metastatic, 39 lymphatic metastases). Immunohistochemistry for E-cadherin, Vimentin, Snail, beta-catenin, Twist, Zeb1 and Podoplanin was performed. RESULTS: Loss of membranous E-cadherin was observed in 77% cSCCs, with no differences between MSCC and non-MSCC. Among the transcriptional factors controlling EMT, no significant Snail1 expression was detected. Twist, Zeb1, Vimentin, beta-catenin and Podoplanin were significantly overexpressed in MSCCs. Twist ectopic expression in SCC13 cells induced Zeb1, Vimentin and Podoplanin expression and E-cadherin delocalization. These changes resulted in a scattered migration pattern in vitro. Expression of EMT markers was decreased in the metastases when compared with the corresponding primary tumors. CONCLUSION: These results suggest that a partial EMT, characterized by the expression of Twist but without a total E-cadherin depletion, is involved in the acquisition of invasive traits by cSCC, but the process is downregulated in lymph node metastases.

Skin-derived precursor cells as an in vitro modelling tool for the study of type 1 neurofibromatosis.

The most characteristic feature of neurofibromatosis type 1 (NF1) is the development of neurofibromas. It has been suggested that these tumors are caused by somatic inactivation of the wild-type NF1 allele, but the cell that originally suffers this mutation remains controversial. Several lines of evidence support the clonal origin of these tumors, and it has been recently suggested that skin-derived precursor cells (SKPs) could be the cell of origin of dermal neurofibromas. Nullizygous (NF1(-/-)) SKPs do give rise to neurofibromas when transplanted to heterozygous mice. Moreover, a nullizygous population of cells that is S100ß negative is present in human neurofibromas, and NF1(+/-) multipotent progenitor cells are seemingly recruited to the tumor. This evidence supports the neurofibroma stem cell hypothesis and a putative involvement of SKPs in the aetiopathogenesis of the disease, suggesting that SKPs could become a valuable tool for the in vitro study of NF1.

Letter: Photodistributed reticulated hyperpigmentation related to diltiazem.

Diltiazem is a calcium channel blocking agent used for the treatment of hypertension. Cutaneous adverse effects are uncommon. The most frequently reported are itching, urticaria, and maculopapular eruption. A peculiar, cutaneous photodistributed reticulated hyperpigmentation secondary to diltiazem has been recently reported. A 66-year-old white woman with a 2 year history of pruritic hyperpigmented lesions on her face was seen in the clinic. Past medical history was remarkable for hypertension, which had been treated with diltiazem. Physical examination showed slate-gray to brown reticulated hyperpigmentation in the photo-exposed areas of the face and neck. Histological examination revealed interface dermatitis with liquefactive degeneration of the basal layer, necrotic keratinocytes, lymphocytic inflammatory infiltrate, and melanophages in the superficial dermis. A diagnosis of diltiazem-induced hyperpigmentation was established and diltiazem was stopped. Gradual resolution of the hyperpigmentation was observed over the following months. Although diltiazem has been marketed for over 20 years, the first cases of this particular type of reticulated hyperpigmentation were described in 2001. Since then, to our knowledge, only 17 cases have been reported in the literature. In all cases, cutaneous lesions appeared at least 6 months after this treatment had been started. Hyperpigmentation was controlled by means of photoprotection and discontinuation of diltiazem. Diltiazem can produce a characteristic lichenoid dermatitis with reticulated hyperpigmentation on sun-exposed areas.

Eritema anular eosinofílico / Eosinophilic annular erythema

Introducción. El eritema anular eosinofílico, inicialmente descrito en la infancia, es una rara enfermedad benigna y autolimitada que se caracteriza por la presencia de lesiones anulares eritematosas recurrentes, que normalmente se localizan en el tronco y las extremidades. El curso es recidivante con intervalos libres de enfermedad. El estudio histológico muestra en la dermis un infiltrado perivascular con linfocitos y eosinófilos. No suele detectarse eosinofilia en sangre periférica. Su etiología es desconocida. El tratamiento con antipalúdicos de síntesis ha demostrado ser eficaz en los 2 casos publicados. Un varón de 59 años consultó por presentar pápulas urticariales y lesiones anulares recurrentes, no pruriginosas, en el tronco, desde hacía 3 meses. La biopsia mostró un infiltrado linfocítico de predominio perivascular con eosinófilos en la dermis. La enfermedad remitió espontáneamente en 10 meses (AU)

PTEN mutations in eight Spanish families and one Brazilian family with Cowden syndrome.

Cowden syndrome is an autosomal dominant genodermatosis, characterized by the presence of multiple hamartomas in the skin, breast, thyroid, gastrointestinal tract, central nervous system, and an increased risk in developing breast and thyroid carcinomas. Over 80 germline mutations of the tumor suppressor gene PTEN, on chromosome 10q23, have been reported in more than 100 unrelated patients and families; however, questions regarding distribution of the mutations in populations from different geographic areas, and phenotypic expression are still unclear. In this study the results are reported of mutation analysis of PTEN in 13 families from Spain and one family of Brazilian origin with Cowden syndrome. PTEN germline mutations were detected in nine of them (64%). Five mutations were located in exon 5, one in exon 6, two in exon 7, and one in exon 8. Four of the mutations were novel. In another case, an identical change had been previously reported as a somatic mutation in an endometrial carcinoma. In one family, the patient presented a de novo mutation, which was not detected in his parents. In five patients, the detection of the PTEN germline mutation confirmed their condition, even in the absence of sufficient criteria to make the clinical diagnosis of Cowden syndrome.