Dysplastic features relevant to malignant transformation in atrophic epithelium of oral submucous fibrosis: a preliminary study

Abstract

Background

The grading of oral epithelial dysplasia (OED) is not applicable to oral submucous fibrosis (OSMF) cases due to the presence of atrophic epithelium. The mucosal margins associated with resected OSCC specimens are often closely related to transformed cells. In this study, we compared the histomorphological alterations (dysplastic features) in the atrophic epithelium of OSMF patients with the mucosal margins of OSCC associated with OSMF (OSCC-OSMF).

Methods

We evaluated 17 dysplastic features in 37 patients with OSMF (biopsy site: buccal mucosa) and 37 patients with OSCC-OSMF (mucosal margins involving buccal mucosa) using histopathological staining.

Results

Dysplastic features, such as keratin pearls within rete ridges, nuclear pleomorphism, and atypical mitotic figures, were not observed in the epithelium of the OSMF or OSCC-OSMF groups. Basal cell hyperplasia (p=0.016), abnormal superficial mitosis (p=0.010), increased nuclear-cytoplasmic ratio (p=0.034), and hyperchromasia (p=0.031) were predominantly seen in the OSCC-OSMF group. We found no statistically significant differences in the following parameters: irregular epithelial stratification (p=1.00), loss of basal cell polarity (p=0.237), presence of drop-shaped rete ridges (p=0.077), increased number of mitotic figures (p=0.154), premature keratinization in single cells (p=0.499), anisonucleosis (p=0.289), anisocytosis (p=0.079), cellular pleomorphism (p=0.317), and increased number and size of nucleoli (p=0.129).

Conclusion

Increased basal cell layer hyperplasia, abnormal superficial mitosis, increased nuclear-cytoplasmic ratio, and hyperchromasia are high-risk features for OSMF, and affected patients should be followed on a priority basis for the early detection of OSCC.

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Altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery

Abstract

Background

Koebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event.

Objectives

To study molecularpathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal.

Methods

We assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long-term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs. We performed immunohistochemistry for p53, p16, Ki-67, TET-2, IDH-2, 5-hmc, and 5-mc. PCR was carried out for the detection of human papilloma viruses. Mutation analysis was performed for BRAF, K-RAS, and EGFR.

Results

All lesions investigated were negative for HPV DNA. Mutations were not detected. Healthy appearing skin of both patients showed relatively high Ki-67, p16, and p53 expression which was comparable to the expression observed in primary SCCs as well as K-SCCs. Protein expression of Ki-67, p16, and mutant p53 was barely detected in the specimens of the healthy controls. A decreased protein expression of TET-2 enzyme was seen in all tumours and healthy appearing skin when compared to the skin of healthy controls.

Conclusions

We observed two patients with K-SCCs developing under DMF treatment. In healthy appearing skin of patients with K-SCCs, wound healing processes, including induction of proliferation and growth factor release, might promote the growth of pre-neoplastic keratinocytes and cancer formation on the basis of pre-existing altered epigenetic pathways and cell cycle dysregulation. Although fumarates can reduce TET-2 expression, the role of DMF intake in the development of K-SCCs remains unclear.

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The measurement of drug-induced interferon-γ releasing cells and lymphocyte proliferation in severe cutaneous adverse reactions

Abstract

Background

The lymphocyte transformation test (LTT) is a standard laboratory method to identify culprit drugs in patients with a history of drug-induced non-immediate hypersensitivity and is mainly performed during the recovery phase. The measurement of drug-specific interferon-γ (IFN-γ)-releasing cells has been introduced to confirm culprit drugs, even during the acute phase of drug allergy.

Objectives

This study aimed to evaluate the capability of the enzyme-linked immunospot assay (ELISpot) to detect drug-specific IFN-γ-releasing cells during the acute phase and the capability of LTT to identify culprit drugs during the recovery phase in patients presenting with severe cutaneous adverse reactions (SCARs).

Methods

Peripheral blood mononuclear cells (PBMCs) from 23 SCAR patients were collected during the acute and recovery phases and assayed for drug-specific IFN-γ-releasing cells and lymphocyte proliferation, respectively.

Results

Drug-specific IFN-γ releasing cells were detectable in 73.9% of SCAR subjects (55.6% and 85.7% in patients who were and were not taking systemic steroids, respectively), whereas LTT results were positive in 52.2% of SCAR subjects. The frequencies of drug-specific IFN-γ-releasing cells were significantly higher in patients with positive LTT than in those with negative LTT (260.1 ± 110.0 and 46.6 ± 20.7 cells/10⁶ PBMCs, P = 0.01). A significant correlation between the results of the IFN-γ ELISpot assay and LTT was demonstrated (r = 0.65, P value < 0.01).

Conclusion

The IFN-γ ELISpot assay could be a useful tool to identify culprit drugs in SCAR patients when culprit drug identification is urgently needed during the acute phase of drug allergy.

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CYLD mutations differentially affect splicing and mRNA decay in Brooke-Spiegler syndrome

Abstract

Brooke-Spiegler syndrome (BSS; OMIM 605041), also known as familial cylindromatosis (OMIM 132700), is an autosomal dominant tumour predisposition disorder characterised by the occurrence of cylindromas, trichoepitheliomas, and spiradenomas.BSS is caused by heterogenous mutations in the CYLD gene. To date, different CYLD mutations have been reported, most of them resulting in a premature termination codon (PTC).² Among these, thirteen splice site mutations have been described. However, it remains largely elusive how such mutations affect splicing.

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Papulopustular rosacea and rosacea-like demodicosis: two phenotypes of the same disease?

Abstract

Background

Papulopustular rosacea and rosacea-like demodicosis have numerous similarities but they are generally considered as two distinct entities, mainly because the causal role of the Demodex mite in the development of rosacea is not yet widely accepted. Several clinical characteristics are traditionally considered to differentiate the two conditions; for example, papulopustular rosacea is typically characterised by central facial papulopustules and persistent erythema, whereas small superficial papulopustules and follicular scales rather suggest rosacea-like demodicosis. However, none of these characteristics is exclusive to either entity.

Objective

To explore differences in Demodex densities according to clinical characteristics traditionally associated with these two conditions.

Methods

Retrospective, observational, case-control study of 242 patients with central face papulopustules. Demodex densities were measured on two consecutive standardised skin surface biopsies.

Results

In the whole cohort, Demodex densities were greater in patients with persistent erythema than in those without. In 132 patients without recent treatment or other facial dermatoses, 120 (91%) had persistent erythema, 119 (90%) small superficial papulopustules, and 124 (94%) follicular scales; 116 (88%) simultaneously had clinical characteristics traditionally associated with both papulopustular rosacea and rosacea-like demodicosis. Higher Demodex densities were linked to the presence of follicular scales, but not to papulopustules size, nor to the presence/absence of persistent erythema.

Conclusion

Our observations highlight the difficulty differentiating between these entities and suggest that rosacea-like demodicosis and papulopustular rosacea should no longer be considered as two separate entities, but rather as two phenotypes of the same disease.

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Influence of cigarette smoking on pemphigus:a systematic review and pooled analysis of the literature

Abstract

Epidemiological evidence suggests that smoking cigarettes may be beneficial in pemphigus, but no systematic evaluation exists to corroborate this assumption. Therefore, a systematic literature review with pooled data analysis of the smoking status in pemphigus patients was conducted. Electronic searches using PubMed from inception to November 2017 identified 13 reports meeting predetermined inclusion and exclusion criteria. Most were case-control studies partly reporting that pemphigus vulgaris and foliaceus occurred less frequently in current and former smokers. Studies also indicated that duration of smoking and number of cigarettes smoked was lower in pemphigus patients than controls and that remission may be achieved sooner in those who smoke. However, although a generally low prevalence of smoking was demonstrated in pemphigus patients, which was lower than in controls by pooled analysis, some investigations found no difference regarding the smoking status compared with non-pemphigus subjects. One study demonstrated more severe mucosal involvement in non-smoking pemphigus patients, whereas another observed no difference in the rate of cutaneous or mucosal lesions between smokers and non-smokers with pemphigus. This review indicates that smoking may be a possible protective factor in pemphigus, although some compromised study methodologies yet hinder any firm conclusion. Further investigations with a refined quality design are required to resolve the so far partly conflicting results in this area.

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Alternative test models for skin aging research

Abstract

Increasing ethical concerns regarding animal experimentation have led to the development of various alternative methods based on the 3Rs (Refinement, Reduction, and Replacement), first described by Russell and Burch in 1959. Cosmetic and skin aging research are particularly susceptible to concerns related to animal testing. In addition to animal welfare reasons, there are scientific and economic reasons to reduce and avoid animal experiments. Importantly, animal experiments may not reflect findings in humans mainly because of the differences of architectures and immune responses between animal skin and human skin. Here we review the shift from animal testing to the development and application of alternative non-animal based methods and the necessity and benefits of this shift. Some specific alternatives to animal models are discussed, including biochemical approaches, two-dimensional and three-dimensional cell cultures, and volunteer studies, as well as future directions, including genome-based research and the development of in silico computer simulations of skin models. Among the in vitro methods, three-dimensional reconstructed skin models are highly popular and useful alternatives to animal models however still have many limitations. With careful selection and skillful handling, these alternative methods will become indispensable for modern dermatology and skin aging research.

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