Biomarkers Found in the Tumor Interstitial Fluid may Help Explain the Differential Behavior Among Keratinocyte Carcinomas.

Basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs) are the most frequent types of cancer, and both originate from the keratinocyte transformation, giving rise to the group of tumors called keratinocyte carcinomas (KCs). The invasive behavior is different in each group of KC and may be influenced by their tumor microenvironment. The principal aim of the study is to characterize the protein profile of the tumor interstitial fluid (TIF) of KC to evaluate changes in the microenvironment that could be associated with their different invasive and metastatic capabilities. We obtained TIF from 27 skin biopsies and conducted a label-free quantitative proteomic analysis comparing seven BCCs, 16 SCCs, and four normal skins. A total of 2945 proteins were identified, 511 of them quantified in more than half of the samples of each tumoral type. The proteomic analysis revealed differentially expressed TIF proteins that could explain the different metastatic behavior in both KCs. In detail, the SCC samples disclosed an enrichment of proteins related to cytoskeleton, such as Stratafin and Ladinin-1. Previous studies found their upregulation positively correlated with tumor progression. Furthermore, the TIF of SCC samples was enriched with the cytokines S100A8/S100A9. These cytokines influence the metastatic output in other tumors through the activation of NF-kB signaling. According to this, we observed a significant increase in nuclear NF-kB subunit p65 in SCCs but not in BCCs. In addition, the TIF of both tumors was enriched with proteins involved in the immune response, highlighting the relevance of this process in the composition of the tumor environment. Thus, the comparison of the TIF composition of both KCs provides the discovery of a new set of differential biomarkers. Among them, secreted cytokines such as S100A9 may help explain the higher aggressiveness of SCCs, while Cornulin is a specific biomarker for BCCs. Finally, the proteomic landscape of TIF provides key information on tumor growth and metastasis, which can contribute to the identification of clinically applicable biomarkers that may be used in the diagnosis of KC, as well as therapeutic targets.

Immunocryosurgery as monotherapy for lentigo maligna or combined with surgical excision for lentigo maligna melanoma.

The incidence of lentigo maligna (LM), in situ (LM) or invasive (lentigo maligna melanoma, LMM), has increased during the last decades. Due to functional or cosmetic outcomes, optimal treatment with surgical excision may not be appropriate in some cases. We tried less invasive therapy, immunocryosurgery, as a single treatment for LM or combined with surgery for LMM, with better aesthetic results. Three patients with LM or LMM not amenable to complete surgical excision were selected. LMM patients underwent limited surgical resection of the invasive area. Subsequently, a combined treatment with topical imiquimod and cryosurgery was performed. The LM patient received immunocryosurgery directly. All of them were free of local and systemic disease at 48, 42 and 41 months after discontinuation of therapy. We consider that immunocryosurgery is an alternative option for LM or even for LMM (after removal of the invasive tissue with narrow margins) in poor surgical candidates, with good therapeutic, functional and cosmetic results.

Epidemiology of Melanocytic Naevi in Children from Lleida, Catalonia, Spain: Protective Role of Sunscreen in the Development of Acquired Moles.

The worldwide incidence of malignant melanoma is increasing. The number of pigmented naevi and amount of solar exposure are important risk factors. The aim of this study was to characterize a paediatric population (from Lleida, Catalonia, Spain) in terms of phenotype, sun behaviour and naevi prevalence. Data on the numbers and distributions of acquired naevi in 369 children, aged 4, 8 and 14 years, were collected and correlated with age, sex, skin phototype and environmental factors (annual/lifetime intermittent and chronic sun exposure, sunburns and sunscreen use). The density of naevi increased with age. Boys had more naevi on the trunk and girls had more naevi on the legs. Children with light skin phototype had more naevi. A higher level of accumulated sun exposure correlated with a higher number of naevi in children with non-adequate sunscreen use. In conclusion, several risk factors associated with naevi density and distribution were found, as previously reported by others. Multivariate analysis confirmed a protective role of sunscreen in the development of acquired melanocytic naevi.

Tenosynovitis with rice body formation presenting as a cutaneous abscess.

A 62-year-old woman with a past medical history of rheumatoid arthritis was referred to the Department of Dermatology because of an enlarging cutaneous lesion on the right thumb which resembled a soft tissue infection. She had received antibiotics without significant improvement. Clinical examination revealed an erythematous nodule involving almost the whole surface of the distal phalanx with spontaneous drainage of countless of small yellowish ovoid granules. Histopathologic study of these structures showed an inner core of amorphous acidophilic material with some interspersed chronic inflammatory cells and a surrounding thin fibrin layer. Special stains and cultures were negative for parasites, bacterium and mycobacterium. Magnetic resonance imaging (MRI) revealed distension of the first and fifth finger flexor sheaths and common finger flexor sheath. These areas were filled by fluid and multiple small nodular lesions. A diagnosis of non-infectious rice body tenosynovitis was rendered and surgical removal was performed. Total recovery was observed with no evidence of recurrence after 6 months of follow-up. To our knowledge, this is the first report of rice body tenosynovitis presenting as a pseudoinflammatory cutaneous lesion with evolution to a cutaneous fistula with drainage of rice grain-like structures. The description of this impressive and peculiar clinical and histopathologic picture is important to further recognize similar cases.

Cyclin D1 localizes in the cytoplasm of keratinocytes during skin differentiation and regulates cell-matrix adhesion.

The function of Cyclin D1 (CycD1) has been widely studied in the cell nucleus as a regulatory subunit of the cyclin-dependent kinases Cdk4/6 involved in the control of proliferation and development in mammals. CycD1 has been also localized in the cytoplasm, where its function nevertheless is poorly characterized. In this work we have observed that in normal skin as well as in primary cultures of human keratinocytes, cytoplasmic localization of CycD1 correlated with the degree of differentiation of the keratinocyte. In these conditions, CycD1 co-localized in cytoplasmic foci with exocyst components (Sec6) and regulators (RalA), and with ß1 integrin, suggesting a role for CycD1 in the regulation of keratinocyte adhesion during differentiation. Consistent with this hypothesis, CycD1 overexpression increased ß1 integrin recycling and drastically reduced the ability of keratinocytes to adhere to the extracellular matrix. We propose that localization of CycD1 in the cytoplasm during skin differentiation could be related to the changes in detachment ability of keratinocytes committed to differentiation.

Inhibition of activated receptor tyrosine kinases by Sunitinib induces growth arrest and sensitizes melanoma cells to Bortezomib by blocking Akt pathway.

Despite the use of multiple therapeutic strategies, metastatic melanoma remains a challenge for oncologists. Thus, new approaches using combinational treatment may be used to try to improve the prognosis of this disease. In this report, we have analyzed the expression of receptor tyrosine kinases (RTKs) in melanoma specimens and in four metastatic melanoma cell lines. Both melanoma specimens and cell lines expressed RTKs, suggesting that they may represent eventual targets for multitargeted tyrosine kinase inhibitor, Suntinib. Sunitinib reduced the proliferation of two melanoma cell lines (M16 and M17) and increased apoptosis in one of them (M16). Moreover, the two metastatic melanoma cell lines harbored an activated receptor (PDGFRα and VEGFR, respectively), and Sunitinib suppressed the phosphorylation of the RTKs and their downstream targets Akt and ribosomal protein S6, in these two cell lines. Similar results were obtained when either PDGFRα or VEGFR2 expression was silenced by lentiviral-mediated short-hairpin RNA delivery in M16 and M17, respectively. To evaluate the interaction between Sunitinib and Bortezomib, median dose effect analysis using MTT assay was performed, and combination index was calculated. Bortezomib synergistically enhanced the Sunitinib-induced growth arrest in Sunitinib-sensitive cells (combination index < 1). Moreover, LY294002, a PI3K inhibitor, sensitized melanoma cells to Bortezomib treatment, suggesting that downregulation of phospho-Akt by Sunitinib mediates the synergy obtained by Bortezomib + Sunitinib cotreatment. Altogether, our results suggest that melanoma cells harboring an activated RTK may be clinically responsive to pharmacologic RTK inhibition by Sunitinib, and a strategy combining Sunitinib and Bortezomib, may provide therapeutic benefit.

Antiproliferative effect of STI571 on cultured human cutaneous melanoma-derived cell lines.

Standard antineoplastic treatment for metastatic melanoma is ineffective in the large majority of patients. Therefore, alternative approaches need to be investigated. STI571 is a new antineoplastic compound, which selectively inhibits the tyrosine kinase activity of ABL, c-Kit and platelet-derived growth factor receptor (PDGFR). Melanoma may express all of these proteins. The aim of this study was to investigate whether STI571 inhibits the in-vitro growth of melanoma cells. Nineteen cell lines were obtained from four primary and 15 metastatic melanomas of cutaneous origin. The percentages of positive cells for the putative targets of STI571 were as follows: ABL, 41-100%; c-Kit, 8-97%; PDGFR-alpha, 41-98%; PDGFR-beta, 51-99%. 3-(4,5-Dimethylthiazol-yl)-2,5-diphenyltetrazolium (MTT) and viability assays showed that STI571 clearly inhibits the proliferation of eight of the 19 (42.1%) cell lines. No relationship could be established between the expression of c-Kit, ABL, PDGFR-alpha or PDGFR-beta and the response of cell lines to STI571. Our study shows, for the first time, an antiproliferative effect of STI571 on human melanoma cell lines of cutaneous origin, raising the possibility of the future clinical use of STI571. The identification of the target of STI571 in human cutaneous melanoma cells would allow the selection of patients who could benefit from this treatment.

Síndrome de Sweet con lesiones ampollosas / Sweet’s syndrome with bullous lesions

Se presenta el caso de un síndrome de Sweet con lesiones atípicas, caracterizadas por placas eritematosas, vesículas y lesiones ampollosas. Las lesiones cutáneas en pacientes con malignidad subyacente son más frecuentemente atípicas y con características vesiculosas, ampollosas o incluso ulcerativas, además de las típicas placas y nódulos. Sin embargo, el caso presentado no se asocia a malignidad a pesar de que el índice de sospecha de estos procesos en particular los hematológicos, debe ser alto

We present a case of Sweet's syndrome with atypical lesions, characterized by erythematous plaques, vesicles and bullous lesions. Skin lesions in patients with an underlying malignancy are more frequently atypical and with vesicular, bullous or even ulcerative characteristics, in addition to the typical plaques and nodules. However, the case presented is not associated with malignancy, despite the fact that these processes, particularly hematologic ones, should be suspected

[Sweet's syndrome with bullous lesions]. / Síndrome de Sweet con lesiones ampollosas.

We present a case of Sweet's syndrome with atypical lesions, characterized by erythematous plaques, vesicles and bullous lesions. Skin lesions in patients with an underlying malignancy are more frequently atypical and with vesicular, bullous or even ulcerative characteristics, in addition to the typical plaques and nodules. However, the case presented is not associated with malignancy, despite the fact that these processes, particularly hematologic ones, should be suspected.