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Diagnosing cutaneous melanomas relies mainly on histopathological analysis, which, in selected cases, can be aided by immunohistochemical evaluation of conventional melanocytic markers. Nevertheless, these malignancies, particularly in metastatic settings, may display divergent differentiation with unusual histological and immunohistochemical features. In this context, we present the case of a 65-year-old male diagnosed with typical superficial spreading melanoma who developed recurrence and metastatic lesions featuring angiosarcomatous differentiation. The diagnosis of the initial tumour and the subsequently dedifferentiated lesions was confirmed by ample immunohistochemical analysis, which included several melanocytic markers, as well as mesenchymal and vascular markers. The recurrent tumour and lymph nodes metastases were completely negative for Melan-A and PRAME, and focally positive for SOX10. Additionally, they also displayed diffuse, intense positivity for CD10 and WT1 and focal positivity for CD99, ERB, and CD31. Thus, the diagnosis of primary cutaneous melanoma with recurrent and metastatic divergent angiosarcomatous differentiation was established. This occurrence is particularly rare and can pose important diagnostic challenges. Therefore, in addition to presenting this highly unusual case, we also performed a comprehensive review of the literature on divergent differentiation in melanomas.

The carcinomas originating from the renal cortex are the most aggressive renal malignancies, with a high tendency for metastasis. Understanding the incidence of cutaneous manifestations caused by renal carcinomas is a challenge. In the first part, this article summarizes a series of factors that promote oncogenesis, invasiveness, and the ability of renal cell carcinoma (RCC) to develop secondary cutaneous manifestations. It is postulated that the cellular stress response is one of the leading causes of developing dermatological events induced by cancers located at distant sites. Furthermore, the paper provides an overview of cutaneous complications associated with renal cancer, categorized as malignant manifestations (metastases, synchronous or metachronous cutaneous malignancies associated with renal cancer), non-malignant indirect cutaneous manifestations associated with renal cancer, and treatment consequences. The data presented in this article suggest that recognizing certain cutaneous disorders could assist the physician in the early identification of renal neoplasms and could lead to a better prognosis.

Background: Lichen planus (LP) is a chronic inflammatory skin disease of unelucidated etiology. LP immunopathogenesis is mainly governed by cytotoxic T lymphocytes that mediate an immune response in basal keratinocytes, which may transform into a reservoir of antigens able to initiate an autoimmune reaction. However, other pathogenic pathways complement these mechanisms. Recent studies highlight the involvement of nitrosative stress in the pathogenesis of chronic inflammatory skin diseases. Current data on its role in the pathogenesis of LP are scarce., Methods: In this article, we investigated nitrosative stress in 40 cutaneous LP (CLP) patients compared to 40 healthy subjects using serum markers including nitrosative stress markers-direct nitrite, total nitrite, nitrate and symmetric dimethylarginine (SDMA), total antioxidant status (TAS), and hsCRP, a marker of inflammation, and analyzed the relationship between nitrosative stress, antioxidant defense, and inflammation to offer new insights into the role of the NO pathway in LP pathogenesis., Results: We identified significantly higher serum levels of direct nitrite, total nitrite, nitrate, SDMA and hsCRP, and significantly lower levels of TAS in CLP patients versus controls. There were significant negative correlations between the serum levels of TAS and significantl positive correlations between the serum levels of hsCRP and the analyzed nitrosative stress markers in patients with CLP., Conclusion: Our results indicate an increased level of nitrosative stress in LP patients that correlates with a pro-inflammatory status and altered antioxidant defense.

Introduction: Research regarding the role of the IL-12 cytokine family in modulating immune and inflammatory responses is continuously evolving. In this study, the contribution of the p35 and p40 subunits as monomers (noted as IL-12p35 and IL-12p40) and heterodimers (noted as IL-12p70 or IL-12p35/p40) was analysed in the pathophysiology and progression of chronic spontaneous urticaria (CSU)., Materials and Methods: We conducted a longitudinal, case-control study involving 42 CSU cases and 40 control cases comprising adults without associated conditions. Serial measurements were performed to assess the serum levels of IL-12p70, IL-12p35, and IL-12p40 at the onset of the disease (pre-therapy phase) and 6 weeks after the initiation of the treatment (post-therapy phase)., Results: During the pre-therapeutic phase of CSU, elevated serum levels of IL-12 cytokine subtypes were detected compared to the control group. The relationship between IL-12 profiles and the course of CSU highlighted the pro-inflammatory role of IL-12p70 and the anti-inflammatory role of IL-12p35. Significant correlations were observed between IL-12p70 levels and the duration of the disease, as well as between IL-12 and the effectiveness of H1-antihistamines., Conclusions: The molecular background for the pleiotropic activities mediated by IL-12-derived cytokines in patients with CSU lies in the strict regulation of the production, signalling pathways, and cytokine-specific influences on the same pathophysiological events. The results of the present study suggest that the superficial layers of the skin serve as a cellular source of IL-12, a cytokine produced through antigenic stimulation. In patients with CSU, we identified independent, additive, or divergent functions of IL-12p70, IL-12p35, and IL-12p40, all relevant to systemic inflammation. These findings prove that the prototype programming of IL-12 is abnormal in CSU.

Cutaneous squamous cell carcinoma (cSCC) arising from the malignant proliferation of epidermal keratinocytes is the second most common skin cancer. Actinic keratosis (AK), which is considered cSCC in situ, may progress into invasive tumors. Currently, there are no serum markers that can differentiate cSCC from AK. The aim of our study was to assess angiogenesis and oxidative stress in patients with cSCC and patients with AK and find reliable serum markers useful in the diagnosis of cSCC. We have determined the serum levels of a group of proangiogenic factors (MMP-2, MMP-9, VEGF, FGF2), the total antioxidative status/capacity (TAS/TAC), ImAnOx, a marker of oxidative stress, and HIF-1 alpha, an indicator of hypoxia. We have identified higher serum levels of MMP-2. MMP-9, VEGF, FGF2 and HIF-1 alpha and lower levels of ImAnOx in cSCC patients compared to AK patients and controls. There were no statistically significant differences between AK patients and controls. We have found positive correlations between proangiogenic markers and HIF-1 alpha and negative correlations between proangiogenic markers and ImAnOx. Our results suggest that MMP-2, MMP-9, VEGF, FGF2, ImAnOx and HIF-1 may be promising markers for differentiating AK from cSCC, and there is a link between angiogenesis, oxidative stress and hypoxia., Competing Interests: The authors declare no conflicts of interest.

Mast cells (MCs) are infamous for their role in potentially fatal anaphylaxis reactions. In the last two decades, a more complex picture has emerged, as it has become obvious that MCs are much more than just IgE effectors of anaphylaxis. MCs are defenders against a host of infectious and toxic aggressions (their interactions with other components of the immune system are not yet fully understood) and after the insult has ended, MCs continue to play a role in inflammation regulation and tissue repair. Unfortunately, MC involvement in pathology is also significant. Apart from their role in allergies, MCs can proliferate clonally to produce systemic mastocytosis. They have also been implicated in excessive fibrosis, keloid scaring, graft rejection and chronic inflammation, especially at the level of the skin and gut. In recent years, the term MC activation syndrome (MCAS) was proposed to account for symptoms caused by MC activation, and clear diagnostic criteria have been defined. However, not all authors agree with these criteria, as some find them too restrictive, potentially leaving much of the MC-related pathology unaccounted for. Here, we review the current knowledge on the physiological and pathological roles of MCs, with a dermatological emphasis, and discuss the MCAS classification.

Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous unit. Its pathogenesis is multifactorial and involves the overlap between four main processes: alteration of the keratinization, increased sebum production, colonization with Cutibacterium acnes , and inflammation. The role of oxidative stress (OS) has been intensively studied in inflammatory skin conditions such as psoriasis, vitiligo, or atopic dermatitis. However, the involvement of OS in the pathogenesis of acne is less known. The evidence accumulated over the last decade suggests that in the case of acne patients, there is an imbalance between oxidants and antioxidants. In this review, we analyzed studies that evaluated markers of OS in patients with acne, published in the last ten years, with the aim of providing new insights into the pathogenesis of acne.

Seborrheic dermatitis (SD) is a relapsing inflammatory skin disorder that affects the seborrheic areas of the body. Its etiology is not completely elucidated; however, the link between disease exacerbations and the proliferation of Malassezia spp., along with the good response to antifungal agents, indicate the role of fungi in its pathophysiology. Sertaconazole nitrate is a relatively new imidazole antifungal agent with a particular structure, consisting in a benzothiophene ring similar to the indole ring of tryptophan, and it acts mainly through the inhibition of ergosterol synthesis and the formation of pores in the fungal cell membrane. The aim of our study was to evaluate the efficiency of sertaconazole 2% cream compared with other topical treatments in patients with SD. We performed an extensive literature search by browsing the PubMed database with the keyword combination "sertaconazole AND seborrheic dermatitis AND clinical trial", which retrieved eight controlled clinical trials evaluating the effects of sertaconazole in SD. All of the clinical trials included a standard scoring index (SI). At 28 days since the beginning of the treatment, the sertaconazole regimen was associated with a significantly higher percentage of patients with mild SI and a lower percentage of patients with moderate or severe SI (odds ratio 0.51) than the other investigated treatments-hydrocortisone, ketoconazole, clotrimazole, metronidazole, pimecrolimus, and tacrolimus (odds ratio 1.95). In conclusion, treatment with sertaconazole 2% cream may represent an efficient alternative therapy for patients with SD., Competing Interests: The authors declare no conflict of interest.

The incidence of melanoma, a very aggressive skin cancer, has increased over the past few decades. Although there are well-established clinical, dermoscopic and histopathological criteria, the diagnosis is often performed late, which has important implications on the patient's clinical outcome. Unfortunately, melanoma is one of the most challenging tumors to diagnose because it is a heterogeneous neoplasm at the clinical, histopathological, and molecular level. The use of reliable biomarkers for the diagnosis and monitoring of disease progression is becoming a standard of care in modern medicine. In this review, we discuss the latest studies, which highlight findings from the genomics, epitranscriptomics, proteomics and metabolomics areas, pointing out different genes, molecules and cells as potential diagnostic and prognostic biomarkers in cutaneous melanoma.

Oxidative stress represents the imbalance between oxidants and antioxidants and has been associated with a wide range of diseases. Thiols are the most important compounds in antioxidant defense. There is an equilibrium between thiols and their oxidized forms, disulfides, known as dynamic thiol-disulfide homeostasis (TDH). In 2014, Erel and Neselioglu developed a novel automated assay to measure thiol and disulfide levels. Subsequently, many researchers have used this simple, inexpensive and fast method for evaluating TDH in various disorders. We have reviewed the literature on the role of TDH in skin diseases. We identified 26 studies that evaluated TDH in inflammatory diseases (psoriasis, seborrheic dermatitis, atopic dermatitis, vitiligo, acne vulgaris and rosacea), allergic diseases (acute and chronic urticaria) and infectious diseases (warts, pityriasis rosea and tinea versicolor). The results are heterogeneous, but in most cases indicate changes in TDH that shifted toward disulfides or toward thiols, depending on the extent of oxidative damage.

Platelet-rich plasma (PRP) represents a novel therapy tested and is used more and more frequently in dermatology and cosmetic surgery for a variety of conditions, including androgenic alopecia (AGA), a common condition with a complex pathogenesis involving genetic factors, hormonal status and inflammation. We performed an extensive literature search which retrieved 15 clinical trials concerning the use in AGA of PRP therapy, alone or in combination, in male, female or mixed patient groups. A quantitative statistical meta-analysis of n = 17 trial groups proved significant increases in hair density from 141.9 ± 108.2 to 177.5 ± 129.7 hairs/cm 2 (mean ± SD) following PRP ( p = 0.0004). To the best of our knowledge, this is the first meta-analysis that proved a statistically significant correlation between the number of PRP treatments per month and the percentage change in hair density ( r = 0.5, p = 0.03), as well as a negative correlation between the mean age of treatment group and the percentage change in hair density ( r = -0.56, p = 0.016). Other factors considered for analysis were the PRP preparation method, amount used per treatment, hair diameter, terminal hairs and pull test. We conclude that PRP represents a valuable and effective therapy for AGA in both males and females if patients are rigorously selected.

Cutaneous squamous cell carcinoma (cSCC), a malignant proliferation of the cutaneous epithelium, is the second most common skin cancer after basal cell carcinoma (BCC). Unlike BCC, cSCC exhibits a greater aggressiveness and the ability to metastasize to any organ in the body. Chronic inflammation and immunosuppression are important processes linked to the development of cSCC. The tumor can occur de novo or from the histological transformation of preexisting actinic keratoses (AK). Malignant cells exhibit a higher amount of sialic acid in their membranes than normal cells, and changes in the amount, type, or linkage of sialic acid in malignant cell glycoconjugates are related to tumor progression and metastasis. The aim of our study was to investigate the sialyation in patients with cSCC and patients with AK. We have determined the serum levels of total sialic acid (TSA), lipid-bound sialic acid (LSA), beta-galactoside 2,6-sialyltransferase I (ST6GalI), and neuraminidase 3 (NEU3) in 40 patients with cSCC, 28 patients with AK, and 40 healthy subjects. Data analysis indicated a significant increase in serum levels of TSA ( p < 0.001), LSA ( p < 0.001), ST6GalI ( p < 0.001), and NEU3 ( p < 0.001) in the cSCC group compared to the control group, whereas in patients with AK only the serum level of TSA was significantly higher compared to the control group ( p < 0.001). When the cSCC and AK groups were compared, significant differences between the serum levels of TSA ( p < 0.001), LSA ( p < 0.001), ST6GalI ( p < 0.001) and NEU3 ( p < 0.001) were found. The rate of synthesis of sialoglycoconjugates and their rate of enzymatic degradation, expressed by the ST6GalI/NEU3 ratio, is 1.64 times lower in the cSCC group compared to the control group ( p < 0.01) and 1.53 times lower compared to the AK group ( p < 0.01). The tumor diameter, depth of invasion, and Ki67 were associated with higher levels of TSA and LSA. These results indicate an aberrant sialylation in cSCC that correlates with tumor aggressiveness.

The interaction of reactive oxygen species (ROS) with lipids, proteins, nucleic acids and hydrocarbonates promotes acute and chronic tissue damage, mediates immunomodulation and triggers autoimmunity in systemic lupus erythematous (SLE) patients. The aim of the study was to determine the pathophysiological mechanisms of the oxidative stress-related damage and molecular mechanisms to counteract oxidative stimuli in lupus nephritis. Our study included 38 SLE patients with lupus nephritis (LN group), 44 SLE patients without renal impairment (non-LN group) and 40 healthy volunteers as control group. In the present paper, we evaluated serum lipid peroxidation, DNA oxidation, oxidized proteins, carbohydrate oxidation, and endogenous protective systems. We detected defective DNA repair mechanisms via 8-oxoguanine-DNA-glycosylase (OGG1), the reduced regulatory effect of soluble receptor for advanced glycation end products (sRAGE) in the activation of AGE-RAGE axis, low levels of thiols, disulphide bonds formation and high nitrotyrosination in lupus nephritis. All these data help us to identify more molecular mechanisms to counteract oxidative stress in LN that could permit a more precise assessment of disease prognosis, as well as developing new therapeutic targets.

Background: The pathogenesis of chronic spontaneous urticaria involves metabolic, immunological, and psychological factors. The thiol-disulfide exchange reactions could be a mechanism to counteract oxidative stress in patients with chronic spontaneous urticaria., Objective: The assessment of thiol-disulfide homeostasis parameters (TDHPs) according to disease severity and the influence of H1-antihistamine therapy in patients with chronic spontaneous urticaria., Material and Method: We have included 30 patients with chronic spontaneous urticaria in the study and we have determined the levels of native thiol, total thiol, disulfides as well as the disulfide/native thiol ratio, disulfide/total thiol ratio and the native thiol/total thiol ratio, before and after therapy with H1-antihistamines., Results: The results of the study showed altered levels of TDHPs and their normalization after treatment with H1-antihistamines in patients with chronic spontaneous urticaria. We determined a statistically significant increase in the serum levels of total thiol, native thiol, and native thiol/total thiol ratio and a significant reduction in the levels of disulfides, disulfide/native thiol ratio and disulfide/total thiol ratio after treatment with H1-antihistamines. The normalization of the serum levels of TDHPs has been associated with the relief of symptoms and reduction or resolution of pruritus and urticarial plaques., Conclusion: These results suggest the involvement of thiol-disulfide homeostasis in the defense against the harmful effects of reactive oxygen species in patients with chronic spontaneous urticaria and the potential role of TDHPs in monitoring H1-antihistamine therapy. To the best of our knowledge, this is the first study investigating TDHPs in patients with chronic spontaneous urticaria before and after treatment.

Lichen planus (LP) is a chronic, immune-mediated inflammatory skin condition that mainly affects the skin (cutaneous LP, CLP) and oral mucosa (oral LP, OLP). However, the mechanisms involved in the pathogenesis of the disease are not fully elucidated. Over time, several theories that could explain the appearance of LP lesions have been postulated. The key players in LP pathogenesis are the inflammatory infiltrate consisting of T cells and the proinflammatory cytokines. The cytokines stimulate the production of reactive oxygen species that induce cell apoptosis, a defining element encountered in LP. The lead inquiry triggered by this revolves around the role of oxidative stress in LP development. There are currently numerous studies showing the involvement of oxidative stress in OLP, but in terms of CLP, data are scarce. In this review, we analyze for the first time the currently existing studies on oxidative stress in CLP and summarize the results in order to assess the role of oxidative stress in skin lesions offering a fresher updated perspective., Competing Interests: The authors declare no conflict of interest.

Basal cell carcinoma (BCC) is the most common malignant skin tumor. BCC displays a different behavior compared with other neoplasms, has a slow evolution, and metastasizes very rarely, but sometimes it causes an important local destruction. Chronic ultraviolet exposure along with genetic factors are the most important risk factors involved in BCC development. Mutations in the PTCH1 gene are associated with Gorlin syndrome, an autosomal dominant disorder characterized by the occurrence of multiple BCCs, but are also the most frequent mutations observed in sporadic BCCs. PTCH1 encodes for PTCH1 protein, the most important negative regulator of the Hedgehog (Hh) pathway. There are numerous studies confirming Hh pathway involvement in BCC pathogenesis. Although Hh pathway has been intensively investigated, it remains incompletely elucidated. Recent studies on BCC tumorigenesis have shown that in addition to Hh pathway, there are other signaling pathways involved in BCC development. In this review, we present recent advances in BCC carcinogenesis.