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Background: Microsatellite instability (MSI) has prognostic value and impacts therapy strategies in several malignancies. Data regarding MSI in melanoma are scarce. The aim of this study was to assess MSI through the analysis of MMR protein expression in patients with melanoma., Methods: An observational retrospective single-center study was designed based on patients with primary melanoma. We assessed MSI through immunohistochemical staining with anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2 on full-thickness excision tissue., Results: Ninety-three patients were included in this study. The complete absence of nuclear staining in tumoral cells was extremely rare, with only one melanoma not expressing MSH6. Most melanomas showed an expression index for MLH1 (77.7%), MSH2 (87.2%), and PMS2 (78.6%) ≥ 75%. Most melanomas (57.8%) exhibited an MSH6 expression index in the range of 1%-74%. A low MSH6 expression index and a reduced combined MMR protein expression index (MMR-e) were significantly associated with higher melanoma-specific survival. A mild PMS2 staining intensity was significantly associated with a higher melanoma-specific survival. The patients with high MMR-e who received immunotherapy progressed and died more frequently than those with reduced MMR-e (75% vs. 33.3%)., Conclusion: More studies are needed to further define the role of MSI in melanoma prognosis and response to immunotherapy., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Vitiligo-like hypopigmentation induced by immune checkpoint inhibitors (ICIs) has been largely associated with improved survival outcomes in metastatic melanoma. However, its development during adjuvant ICI therapy and its role as a prognostic factor in this setting remain unclear. We aimed to describe ICI-induced vitiligo in a cohort of patients with resected stage III melanoma treated with adjuvant ICI and to identify differences in progression-free survival (PFS) and distant metastasis-free survival (DMFS) between those who developed vitiligo and those who did not. Patients and data were collected from two institutions, both retrospectively and prospectively, from January 2018 to February 2024. Patients were divided into 'vitiligo' and 'non-vitiligo' groups for comparisons. Of 40 patients, 22.5% developed ICI-induced vitiligo [median follow-up: 23 months (1-73)]. Treatments received were nivolumab (70%) and pembrolizumab (30%). Fifty-five percent of the patients completed 1 year of treatment, 37.5% discontinued and 7.5% were still ongoing. Vitiligo and non-vitiligo groups differed in the cause of treatment discontinuation (severe toxicity in vitiligo vs. progression in non-vitiligo, P = 0.005) and the occurrence of progression (none in vitiligo vs. 52% in non-vitiligo, P = 0.001). Survival analyses showed longer PFS in vitiligo group (P = 0.013) and no differences in DMFS (P = 0.111). ICI-induced vitiligo typically affected photo-exposed areas, with a median time to onset of 4 months (1-27). These preliminary results on ICI-induced vitiligo in adjuvant treatment are in agreement with those reported in advanced melanoma treatment, so its development in the adjuvant setting could be a sign of good prognosis as well., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Hematopoietic stem cell transplantation (HSCT) has improved outcomes for severe hematologic, malignant, and immune disorders, yet poses an increased risk of subsequent malignancies. This study aimed to examine the risk of skin cancer following HSCT and identify potential risk factors. The search was conducted in MEDLINE, EMBASE, and CINAHL databases until December 2023. Cohort studies reporting standardized incidence ratios (SIRs) for post-HSCT skin cancer or investigating risk factors were included. SIRs, or hazard ratios (HRs) with 95% confidence interval (CI), were calculated using random-effects inverse-variance models. Outcome endpoints were SIRs of skin cancer post-HSCT and risk factors, including gender, chronic graft-versus-host disease (cGVHD), voriconazole exposure, and total body irradiation (TBI). Twenty-six studies involving 164,944 HSCT recipients (allogeneic HSCT, n = 68,637; autologous HSCT, n = 95,435; mean age: 38.5 ± 13.8 years; 71,354 females [43.3%]) were analyzed. Overall, SIR for skin cancer post-HSCT was 7.21 (95% CI 3.98-13.08), with SIRs of 2.25 (95% CI: 1.37-3.68) for autologous HSCT, and 10.18 (95% CI 5.07-20.43) for allogeneic HSCT. Risk factors for skin cancer risk included cGVHD (HR = 2.86 [95% CI: 2.01-4.07]), specifically for basal cell and squamous cell carcinoma (SCC) (HR = 1.80 [95% CI: 1.31-2.46] and HR = 3.68 [95% CI: 2.39-5.68], respectively), male gender (HR = 1.56 [95% CI: 1.15-2.13]), especially for SCC (HR = 1.70 [95% CI: 1.03-2.80]), and voriconazole exposure (HR = 2.01 [95% CI: 1.12-3.61]). TBI showed no statistically significant association with subsequent skin cancer (HR = 1.12 [95% CI: 0.73-1.71]). These findings highlight the importance of rigorous skin cancer surveillance and preventive strategies in HSCT recipients, particularly in male individuals undergoing allogeneic transplants and those with identifiable risk factors, to enable early detection and intervention., (© 2024 the International Society of Dermatology.)

Scalp melanomas (SM) have been previously associated with poor overall and melanoma-specific survival rates. The aim of this study was to describe and compare the clinicopathological characteristics and survival outcomes of SM and non-scalp cutaneous head and neck melanoma (CHNM). An observational multi-center retrospective study was designed based on patients with CHNM followed in two tertiary care hospitals. A hundred and fifty-two patients had CHNM, of which 35 (23%) had SM. In comparison with non-scalp CHNM, SM were more frequently superficial spreading and nodular subtypes, had a thicker Breslow index median (2.1 mm vs. 0.85 mm), and a higher tumor mitotic rate (3 vs. 1 mitosis/mm 2 ) ( p < 0.05). SM had a higher risk of recurrence and a higher risk of melanoma-specific death ( p < 0.05). In the multivariate analysis, scalp location was the only prognostic factor for recurrence, and tumor mitotic rate was the only prognostic factor for melanoma-specific survival. We encourage routinely examining the scalp in all patients, especially those with chronic sun damage.

The association of multiple pilomatricomas with xeroderma pigmentosum has not been described. We report a case of a child with multiple pilomatricomas and photosensitivity who was found to have a pathogenic variant in exon 4 of XPA and a likely pathogenic variant in COL6A1., (© 2022 Wiley Periodicals LLC.)

Multiple primary melanomas (MPM) refer to the occurrence of more than one synchronous or metachronous melanoma in the same individual. The aim of this study was to identify the frequency of MPM and describe the clinical and histopathologic characteristics of patients with MPM. An observational single-center retrospective study was designed based on a cohort of melanoma patients followed in a tertiary care hospital. Fifty-eight (8.9%) patients developed MPM. Most patients were men (65.5%) and the median age at the time of diagnosis of the first melanoma was 71 years old. The median time of diagnosis of the second melanoma from the first melanoma was 10.9 months, and 77.6% of second melanomas were diagnosed within the first 5 years. In total, 29 (50%) and 28 (48.3%) first and second melanomas were located in the trunk, respectively. Concordance of anatomic site between primary and subsequent melanoma was found in 46.6% of the patients. Proportion of in situ melanomas was increasingly higher in subsequent melanomas (from 36.21% of first melanomas to 100% of fifth melanomas). An increasing rate of melanomas with histological regression was observed within subsequent melanomas (from 60.3% of first melanomas to 80% of third melanomas). Our results support the importance of careful long-term follow-up with total body examination in melanoma patients.

The therapeutic value of sentinel lymph node biopsy (SLNB) in thin melanoma remains controversial. The aim of this study is to determine the role of SLNB in the survival of thin melanomas (≤1 mm). A multicenter retrospective observational study was designed. A propensity score matching was performed to compare patients who underwent SLNB vs. observation. A multivariate Cox regression was used. A total of 1438 patients were matched by propensity score. There were no significant differences in melanoma-specific survival (MSS) between the SLNB and observation groups. Predictors of MSS in the multivariate model were age, tumor thickness, ulceration, and interferon treatment. Results were similar for disease-free survival and overall survival. The 5- and 10-year MSS rates for SLN-negative and -positive patients were 98.5% vs. 77.3% ( p < 0.001) and 97.3% vs. 68.7% ( p < 0.001), respectively. SLNB does not improve MSS in patients with thin melanoma. It also had no impact on DSF or OS. However, a considerable difference in MSS, DFS, and OS between SLN-positive and -negative patients exists, confirming its value as a prognostic procedure and therefore we recommend discussing the option of SLNB with patients.

Recent evidence suggests the existence of a miRNA regulatory network involving human telomerase reverse transcriptase gene ( hTERT ), with miR-138-5p playing a central role in many types of cancers. However, little is known about the regulation of hTERT expression by microRNA (miRNAs) in melanocytic tumors. Here, we investigated the effects of miR-138-5p in hTERT regulation in melanoma cells lines. In vitro studies demonstrated higher miR-138-5p and lower hTERT messenger RNA (mRNA) expression in human epidermal melanocytes, compared with melanoma cell lines (A2058, A375, SK-MEL-28) by quantitative polymerase chain reaction (qPCR) observing a negative correlation between them. A2058 melanoma cells were selected to be transfected with miR-138-5p mimic or inhibitor. Using luciferase assay, hTERT was identified as a direct target of this miRNA. Overexpression of miR-138-5p detected by Western blot revealed a decrease in hTERT protein expression ( p = 0.012), and qPCR showed a reduction in telomerase activity ( p < 0.001). Moreover, suppressions in cell growth ( p = 0.035) and migration abilities ( p = 0.015) were observed in A2058-transfected cells using thiazolyl blue tetrazolium bromide and flow cytometry, respectively. This study identifies miR-138-5p as a crucial tumor suppressor miRNA involved in telomerase regulation. Targeting it as a combination therapy with immunotherapy or targeted therapies could be used in advanced melanoma treatment; however, more preclinical studies are necessary.

Several studies have focused on identifying microRNAs involved in the pathogenesis of melanoma. However, its association with clinicopathological features has been scarcely addressed. The aim of this study is to identify microRNAs expression profiles related to aggressive clinicopathological and molecular features, and to analyze the association with melanoma survival. A retrospective and observational study was performed in a series of 179 formalin-fixed paraffin embedded primary cutaneous melanomas. First, a screening analysis on a discovery set (n = 22) using miRNA gene chip array (Affymetrix, Santa Clara, California, USA) was performed. Differentially expressed microRNAs were detected employing the software Partek Genomic Suite. Validation of four microRNAs was subsequently performed in the entire series (n = 179) by quantitative real time PCR (qRT-PCR). MicroRNAs expression screening analysis identified 101 microRNAs differentially expressed according to Breslow thickness (≤1 mm vs. >1 mm), 79 according to the presence or absence of ulceration, 78 according to mitosis/mm2 (<1 mitosis vs. ≥1 mitosis) and 97 according to the TERT promoter status (wt vs. mutated). Six microRNAs (miR-138-5p, miR-130b-3p, miR-30b-5p, miR-34a-5p, miR-500a-5p, miR-339-5p) were selected for being validated by qRT-PCR in the discovery set (n = 22). Of those, miR-138-5p, miR-130b-3p, miR-30b-5p, miR-34a-5p were selected for further analysis in the entire series (n = 179). Overexpression of miR-138-5p and miR-130b-3p was significantly associated with greater Breslow thickness, ulceration, and mitosis. TERT mutated melanomas overexpressed miR-138-5p. Kaplan-Meier survival analysis showed poorer survival in melanomas with miR-130b-3p overexpression. Our findings provide support for the existence of a microRNA expression profile in melanomas with aggressive clinicopathological features and poor prognosis., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Epidermal necrolysis (EN) compromises a spectrum of life-threatening dermatoses (Stevens-Johnson Syndrome [SJS], overlap syndrome and toxic epidermal necrolysis [TEN]). Currently, no active therapeutic regimen with unequivocal benefit exists for SJS/TEN. SCORTEN is the widely-used prognostic scale specific for SJS/TEN. Nevertheless, a new prognostic scale, the ABCD-10, has been recently proposed. In this context, acute renal failure (ARF) seems to be an important comorbidity that could influence prognosis in SJS/TEN patients more than it is assumed by these two scales. Our objectives were to compare the accuracy of the SCORTEN and ABCD-10 scales in predicting the mortality in SJS/TEN, and to investigate the influence of renal failure on prognosis. The prognostic results of 18 patients with EN treated in two referral centers between 2013 and 2018 are presented. SCORTEN, ABCD-10 and renal function values were retrospectively collected for all patients. Out of the 18 patients who were analyzed, nine (50%) received only supportive therapy, four were treated with etanercept 50 mg in a single dose (22.2%) and five with corticosteroids (27.8%). Five patients developed ARF. Predicted mortality was 3.48 for SCORTEN and 2.33 for ABCD-10. Eventually, four patients died (22.2%), all had ARF and none of them received active treatment. Despite study limitations and in the absence of active treatment of choice, SCORTEN behaved as a reliable predictor of mortality in patients with EN, outperforming the newer ABCD-10. ARF was an early event associated with a poor prognosis, which could represent a prognostic marker to consider in the future., (© 2020 Japanese Dermatological Association.)

Background: Melanocytic acral nevi have a series of distinguishing features, including their location, patient age at onset, clinical progression, and histological findings. In particular, histopathological analysis often reveals a melanocytic acral nevus with intraepidermal ascent of cells (MANIAC nevus), which in some cases can be mistaken for atypia or malignancy., Aim: This study describes the clinicopathological characteristics of acral nevi in patients under 18 years old and contrasts the clinical and histological features between MANIAC vs non-MANIAC nevi., Methods: This was a retrospective observational study, performed in our department in the decade between January 2007 and January 2017. We included patients younger than 18 years of age who were subjected to the removal of melanocytic acral nevi., Results: A total of 70 patients were studied. 54.2% (38/70) were females and 45.8% (32/70) were males. With regard to the type of nevus, 34 were compound, 27 were junctional, and 9 were predominantly intradermal lesions. We identified a total of 41 MANIAC nevi and 29 non-MANIAC nevi. Statistically significant differences between these two groups were identified in nevus size (larger in MANIAC) and the frequency of compound nevi (higher in the MANIAC group), but not in the remainder of the histological parameters studied., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Promoter methylation of tumour suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over 100 genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated., Objectives: This is a retrospective observational study that aims to analyse the prevalence of CpG island methylation in a series of primary melanomas, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival., Materials and Methods: DNA methylation was analysed using methylation-specific multiplex ligation-dependent probe amplification in a series of 170 melanoma formalin-fixed paraffin-embedded tumour samples. The relationship between the methylation status, known somatic mutations and clinicopathological features was evaluated. Disease-free survival (DFS) and overall survival (OS) were displayed by the Kaplan-Meier method., Results: In the entire cohort, one or more genes were detected to be methylated in 55% of the patients. The most prevalent methylated genes were RARB 31%, PTEN 24%, APC 16%, CDH13 16%, ESR1 14%, CDKN2A 6% and RASSF1 5%. An association between aberrant methylation and aggressive clinicopathological features was observed (older age, increased Breslow thickness, presence of mitosis and ulceration, fast-growing melanomas, advancing stage and TERT mutations). Furthermore, Kaplan-Meier survival analysis showed a correlation of methylation and poorer DFS and OS., Conclusions: Aberrant methylation of TSGs is a frequent event in melanoma. It is associated with aggressive clinicopathological features and poorer survival. Epigenetic alterations may represent a significant prognostic marker with utility in routine practice., (© 2018 British Association of Dermatologists.)

Purpose: The use of radiation therapy (RT) for non-melanoma skin cancer (NMSC) has been changing throughout the last century. Over the last decades, the use of radiotherapy has surged with the development of new techniques, applicators, and devices. In recent years, electronic brachytherapy (eBT) devices that use small x-ray sources have been introduced as alternative to radionuclide dependence. Nowadays, several devices have been incorporated, with a few series reported, and with a short follow-up, due to the recent introduction of these systems. The purpose of this work is to describe the clinical results of our series after two years follow-up with a specific eBT system., Material and Methods: This is a prospective single-center, non-randomized pilot study, to assess clinical results of electronic brachytherapy in basal cell carcinoma using the Esteya ® system. In 2014, 40 patients with 60 lesions were treated. Patient follow-up on a regular basis was performed for a period of two years., Results: Twenty-six patients with 44 lesions achieved two years follow-up. A complete response was documented in 95.5% of cases. Toxicity was mild (G1 or G2) in all cases, caused by erythema, erosion, or alopecia. Cosmesis was excellent in 88.6% of cases, and good in the rest. Change in pigmentation was the most frequent cosmetic alteration., Conclusions: This work is special, since the equipment's treatment voltage was 69.5 kV, and this is the first prospective study with long term follow-up with Esteya ® . These preliminary report show excellent results with less toxicity and excellent cosmesis. While surgery has been the treatment of choice, certain patients might benefit from eBT treatment. These are elderly patients with comorbidities or undergoing anticoagulant treatment as well as those who simply refuse surgery or might have other contraindications., Competing Interests: Authors report no conflict of interest.

Molecular diagnostics are increasingly performed routinely in the diagnosis and management of patients with melanoma due to the development of novel therapies that target specific genetic mutations. The development of next-generation sequencing (NGS) technologies has enabled to sequence multiple cancer-driving genes in a single assay, with improved sensitivity in mutation detection. The main objective of this study was the design and implementation of a melanoma-specific sequencing panel, and the identification of the spectrum of somatic mutations in a series of primary melanoma samples. A custom panel was designed to cover the coding regions of 35 melanoma-related genes. Panel average coverage was 2,575.5 reads per amplicon, with 92,8% of targeted bases covered ≥500×. Deep coverage enabled sensitive discovery of mutations in as low as 0.5% mutant allele frequency. Eighty-five percent (85/100) of the melanomas had at least one somatic mutation. The most prevalent mutated genes were BRAF (50%;50/199), NRAS (15%;15/100), PREX2 (14%;14/100), GRIN2A (13%;13/100), and ERBB4 (12%;12/100). Turn-around-time and costs for NGS-based analysis was reduced in comparison to conventional molecular approaches. The results of this study demonstrate the cost-effectiveness and feasibility of a custom-designed targeted NGS panel, and suggest the implementation of targeted NGS into daily routine practice.

Purpose: Surface electronic brachytherapy (EBT) is an alternative radiotherapy solution to external beam electron radiotherapy and high-dose-rate radionuclide-based brachytherapy. In fact, it is also an alternative solution to surgery for a subgroup of patients. The objective of this work is to confirm the clinical efficacy, toxicity and cosmesis of a new EBT system, namely Esteya(®) in the treatment of nodular and superficial basal cell carcinoma (BCC)., Material and Methods: This is a prospective single-center, non-randomized pilot study to assess the efficacy and safety of EBT in nodular and superficial BCC using the Esteya(®) system. The study was conducted from June 2014 to February 2015. The follow up time was 6 months for all cases., Results: Twenty patients with 23 lesions were included. A complete response was documented in all lesions (100%). A low level of toxicity was observed after the 4(th) fraction in all cases. Erythema was the most frequent adverse event. Cosmesis was excellent, with more than 60% of cases without skin alteration and with subtle changes in the rest., Conclusions: Electronic brachytherapy with Esteya(®) appears to be an effective, simple, safe, and comfortable treatment for nodular and superficial BCC associated with excellent cosmesis. It could be a good choice for elderly patients, patients with contraindications for surgery (due to comorbidities or anticoagulant drugs) or patients where surgery would result in a more disfiguring outcome. A longer follow-up and more studies are needed to confirm these preliminary results.

Background: Mycosis fungoides (MF) is the most frequent type of cutaneous T cell lymphoma. Its clinicopathological spectrum is wide, and the resulting diversity makes it difficult to establish a differential diagnosis among pityriasis lichenoides (PL), lymphomatoid papulosis (LyP), and atypical MF., Objectives: This study describes four patients with longstanding PL-like lesions, in whom clinicopathological correlations contributed towards the establishment of definitive diagnoses of MF., Methods: The clinical histories of the four patients were reviewed. Skin biopsies were processed by hematoxylin and eosin staining and immunohistochemical techniques. Disease spread was studied according to laboratory tests, complete blood counts, biochemical parameters, lactate dehydrogenase, lymphocyte populations, and Sézary cells. Thoracoabdominopelvic computed tomography was performed., Results: The four patients included two women and two men, aged 35-70 years, all of whom had chronic skin lesions located mainly on the trunk and extremities. In three patients, initial clinicopathological correlations led to the diagnosis of PL; further biopsies were required to diagnose MF. In all patients, the atypical lymphocytic infiltrate showed a lichenoid or perivascular distribution with focal epidermotropism and parakeratosis. All cases proved positive for CD4 and CD3, and negative for CD20, CD8, and CD30. Polymerase chain reaction showed monoclonal-type T cells in one and polyclonal infiltrates in three patients. All patients were initially treated with topical corticosteroids and photochemotherapy. None of the treatments proved completely successful, but subsequent tests have yielded no evidence of disease progression in any patient., Conclusions: In patients with clinical features of longstanding PL and histological findings consistent with MF, differential diagnosis must include PL, LyP, and papular MF. As some forms of PL evolve towards MF and PL-like forms of MF, these patients should undergo regular follow-up and repeated biopsies in order to discard diagnoses of atypical forms of MF., (© 2014 The International Society of Dermatology.)

Epstein-Barr virus-positive (EBV) diffuse large B-cell lymphoma (DLCBL) of the elderly is a newly described lymphoproliferative disorder that arises in elderly patients without a predisposing immunodeficiency. Clinical features at presentation may include lymphadenopathy, B-symptoms and extranodal involvement. The main sites of extranodal involvement are the skin, lung, tonsil and stomach. Histopathological findings include atypical large lymphoid cells with variable amounts of reactive cells, such as small lymphocytes, plasma cells and histiocytes. The neoplastic cells are positive for CD20, and in situ hybridization for EBV-encoded RNA is positive in the majority of neoplastic cells. We present a new case of EBV-positive DLBCL in an 85-year-old man, who presented to our clinic with a 2-month history of asymptomatic cutaneous lesions involving his face and scalp., (© 2014 British Association of Dermatologists.)

Psoriasis is a systemic chronic inflammatory disease that affects 1-3% of the world's population. Knowledge of the pathogenesis of psoriasis, particularly in the understanding of the role of T cells and tumor necrosis factor α (TNFα), and advances in immunology have led to the development of biological agents, which, due to their great effectiveness, speed of response and good tolerability, have revolutionized patient management. One of these is infliximab, a human chimeric immunoglobulin G1 monoclonal antibody composed of human antibody constant regions and murine variable regions that was developed specifically to target TNFα. The six cases presented in this series highlight the feasibility, efficacy and safety of infliximab for psoriasis when administered in a variety of patients in several infusion centers across Spain. All six patients showed improvement in their psoriasis after the initiation of infliximab and no significant tolerability issues or injection site reactions were reported, despite the presence of several comorbid conditions or patient characteristics that traditionally reduce the efficacy of psoriasis treatments. This suggests that while the management of psoriasis patients with comorbid conditions and various unfavorable prognostic characteristics requires a multidisciplinary approach to ensure the patient obtains the best therapeutic response, infliximab is an effective and well tolerated treatment in these patients.

Palisaded neutrophilic granulomatous dermatitis (PNGD) is a rare neutrophilic dermatosis that shows a broad clinical and histopathological spectrum. The clinical presentation of PNGD varies from asymptomatic papules, to nodules, to annular plaques. The most common clinical presentation is erythematous papules on the extensor surface of extremities, especially fingers and elbows. Histopathological findings demonstrate a spectrum of changes that reflect the evolution of the lesions, from only sparse mixed perivascular infiltrates to interstitial or palisaded granuloma formation with dermal fibrosis. The cause of PNGD is unknown, but there is a prominent association with systemic conditions, particularly with autoimmune diseases, representing rheumatoid arthritis and systemic lupus erythematosus, the most common associations. It has also been described associated to systemic sclerosis, sarcoidosis, systemic vasculitis, inflammatory bowel disease, and lymphoproliferative disorders, and also drugs have been implicated. Recently, it has been described the potential association with tumor necrosis factor alpha inhibitors. This dermatosis should be considered as a marker of systemic disease and particularly it should be considered in patients with history of autoimmune disorders who present with papular eruptions on the extremities.