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Background: Following the pivotal phase II trial BOLT, the Hedgehog (Hh) inhibitor sonidegib was approved in the EU to treat locally advanced basal cell carcinoma (laBCC) in patients not amenable to surgery or radiotherapy. We report safety data from the interim analysis of the real-world NISSO study., Methods: NISSO is an ongoing non-interventional, multinational, post-authorization safety study (NCT04066504). Patients with laBCC are treated with sonidegib 200 mg orally once daily and followed for 3 years. Dose modifications were allowed according to the local prescribing information., Results: Between May 6, 2019, and March 15, 2022, 321 patients with laBCC were enrolled at 46 European sites (data cut-off: June 22, 2023). Treatment was discontinued in 241 (75.1%) patients, with the main reasons being the patient/guardian decision (n = 69, 28.6%), treatment success (n = 40, 16.6%) and the physician decision (n = 35, 14.5%). The median duration of sonidegib exposure was 8.8 months (4.4-13.7 months). Overall, 284 (88.5%) patients had ≥ one treatment-emergent adverse event (TEAE). Most TEAEs were ≤ grade 2 and the most common were muscle spasms (n = 141; 43.9%), dysgeusia (n = 119; 37.1%), and alopecia (n = 97; 30.2%). After 3 months of treatment, the cumulative rates of muscle spasms, dysgeusia, and alopecia were 21.8%, 16.2%, and 3.7%, respectively. TEAEs led to treatment discontinuation in 59 (18.4%) patients, while 149 (46.4%) patients had at least one TEAE leading to dose reduction or interruption. Serious drug-related TEAEs were reported in 13 (4.1%) patients., Conclusions: These results confirm the safety profile previously observed. Most patients experienced the onset of common TEAEs after 3 months of treatment, and the cumulative incidence of most common TEAEs was 10-20% lower compared to the BOLT study, except for dysgeusia and fatigue that had a similar incidence. The percentage of patients experiencing TEAEs requiring interruption or dose reduction was similar to the BOLT study, while the proportion of patients with TEAE leading to discontinuation of sonidegib was lower. This study demonstrates that the tolerability of sonidegib is manageable in routine clinical practice., Trial Registration: NCT04066504., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved by ethics committees of participating study centers: Ethics Committee of the MHH Hannover; Ethics Committee of Westphalia-Lippe; Ethics Committee of the Christian-Albrechts-Universität zu Kiel; Ethics Committee of the Saxony-Anhalt Medical Association; Ethics Committee of the Medical Association of Thuringia; Ethics Committee of the Medical Faculty of the University of Duisburg-Essen; Ethics Committee of the University of Tübingen; Ethics Committee of the Albert-Ludwigs-University Freiburg; Ethics Committee of the Medical Association of Lower Saxony; Ethics Committee of the University of Regensburg; Ethics Committee of the University of Lübeck; Ethics Committee of the Rhineland-Palatinate Medical Association; Ethics Committee of the Medical Association of Hesse; Ethics Committee of the North Rhine Medical Association; Ethics Committee of the Medical Faculty of the Ruhr University Bochum; Ethics Committee of the Goethe University Frankfurt; Ethics Committee Hamburg; Ethics Committee of the University of Ulm; Ethics Committee of the Technical University of Munich; Ethics Committee Bad Oeynhausen; Ethics Committee at the Technical University of Dresden; Ethics Committee Berne; Ethics Committee Zurich; Comitato Etico Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale"; Comitato Etico I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”; Comitato Etico Interaziendale Novara; Comitato Etico Università Federico II; Comitato Etico Fondazione Policlinico Universitario Agostino Gemelli IRCCS – Università Cattolica del Sacro Cuore; Comitato Etico ASL Avezzano/Sulmona/L’Aquila Teramo; Comitato Etico Regionale Liguria; Comitato Etico di Area Vasta Centro; Comitato Etico Fondazione IRCCS “Istituto Nazionale dei Tumori”; Comitato Etico Istituto Dermopatico dell’Immacolata – IRCCS; Comitato Etico di Brescia; Comitato Etico della Romagna (CEROM); Ethics Committee for Clinical Research of Hospital Clínic of Barcelona; Ethics Committee of Hospital of Nuestra Señora de la Candelaria; Ethics Committee of Hospital of Ramón y Cajal; Research Ethics Committee / Ethics Committee for Drug Research of the Dr. Negrín University Hospital of Gran Canaria; Ethics Committee of Galicia (SERGAS); Ethics Committee of the Hospital of Vall d'Hebron; Ethics Committee of University Hospital of La Paz; Ethics Committee of Hospital of Santa Creu i Sant Pau; Ethics Committee of Hospital of La Fe; Ethics Committee of University General Hospital of Valencia; Ethics Committee of Hospital of Germans Trias i Pujol; Ethics Committee of University Hospital of Vírgen de la Macarena (site was not initiated). Consent for publication Not applicable. Competing interests RG served as consultant for BristolMyers Squibb, MerckSharpDohme, Novartis, GlaxoSmithKline, Amgen, Almirall-Hermal, Pierre-Fabre, SUN Pharma, Immunocore, Delcath, Merck Healthcare, Sanofi/Regeneron. RG received honoraria for lectures from BristolMyers Squibb, MerckSharpDohme, Novartis, Amgen, Merck Healthcare, Almirall-Hermal, Pierre-Fabre, Sanofi/Regeneron, SUN Pharma. RG received travel support from Pierre-Fabre, SUN Pharma, Boehringer Ingelheim. RG received research grants from Sanofi/Regeneron, Merck Healthcare, Amgen, SUN Pharma, KyowaKirin, Almirall-Hermal. UL served as a consultant to MSD, Novartis, Sanofi, Sun Pharma, received travel support from Sun Pharma and Pierre Fabre, speakers’ fees from Sun Pharma, Sanofi, MSD, Novartis and institutional grants from MSD, outside the submitted work. PM received honoraria for lectures and presentations from MSD, Novartis, BMS, Pierre Fabre, Sanofi Genzyme, Immunocore, Delcath, Almirall Hermal, Sun Pharma, Regeneron. PM received travel support from MSD, BMS, Sun Pharma, Novartis and served as consultant for Novartis, BMS, Pierre Fabre, Sanofi Genzyme, Beiersdorf, MSD, Beiersdorf, Biotech, Regeneron, Sun Pharma. KCK serves as consultant to Philogen, BMS, MSD, Sanofi Aventis, Immunocore and received travel grants and speaker fees from Philogen, Pierre Fabre, BMS, MSD, Sun Pharma, Sanofi Aventis, Novartis, Medac and has received research support from Novartis. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Boehringer-Ingelheim, Regeneron, Pfizer, Nouscom, Lunaphore, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca, Philogen, Biontech, Anaveon. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi and travel support from Pfizer, Bio-Al Health, Replimmune, MSD, Pierre Fabre, Philogen. MS declares no conflicts of interest. KP reports grants and personal fees from Sanofi, Novartis, Abbvie, Almirall, Philogen, Leo Pharma, Lilly, Janssen, Pierre Fabre, Sun Pharma, Biogen, Galderma. KP received speaker fees from Lilly, Sanofi, Sun Pharma. GMPP has conflicts of interest with Sun Pharma, Almirall and La Roche-Posay. RFdM has/had a consultant/advisory role for Takeda, Kyowa Kirin, Recordati, Sun Pharma and received travel support from Kyowa Kirin, Sun Pharma, Janssen, UCB. RBE and REH have no conflicts of interest to state. AH reports grants and personal fees from Agenus, Almirall, Amgen, BMS, CureVac, Dermagnostix, Eisai, Highlight Therapeutics, Huya Biosciences, IO Biotech, Immunocore, Incyte, Iovance, Kyowa Kirin, MerckPfizer, MSD/Merck, NeraCare, Novartis Pharma, Philogen, Pierre Fabre, Replimune, Regeneron, Roche, Sanofi-Genzyme, Seagen, Xenthera, and from Sun Pharma outside the submitted work. SM, NG, and RA are employees of Sun Pharmaceuticals Industries and SUN Pharmaceuticals Germany GmbH., (© 2024. The Author(s).)

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers., (© 2024. The Author(s).)

Skin cancer (SC) is one of the three most common cancers worldwide. Melanoma has the deadliest potential to spread to other parts of the body among all SCs. For SC treatments to be effective, early detection is essential. The high degree of similarity between tumor and non-tumors makes SC diagnosis difficult even for experienced doctors. To address this issue, authors have developed a novel Deep Learning (DL) system capable of automatically classifying skin lesions into seven groups: actinic keratosis (AKIEC), melanoma (MEL), benign keratosis (BKL), melanocytic Nevi (NV), basal cell carcinoma (BCC), dermatofibroma (DF), and vascular (VASC) skin lesions. Authors introduced the Multi-Grained Enhanced Deep Cascaded Forest (Mg-EDCF) as a novel DL model. In this model, first, researchers utilized subsampled multigrained scanning (Mg-sc) to acquire micro features. Second, authors employed two types of Random Forest (RF) to create input features. Finally, the Enhanced Deep Cascaded Forest (EDCF) was utilized for classification. The HAM10000 dataset was used for implementing, training, and evaluating the proposed and Transfer Learning (TL) models such as ResNet, AlexNet, and VGG16. During the validation and training stages, the performance of the four networks was evaluated by comparing their accuracy and loss. The proposed method outperformed the competing models with an average accuracy score of 98.19%. Our proposed methodology was validated against existing state-of-the-art algorithms from recent publications, resulting in consistently greater accuracies than those of the classifiers.

Nonmelanoma skin cancers (NMSC), comprising basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are typically encountered on photo-exposed skin. Nevertheless, several cases of NMSC have been described in covered areas such as the genital region; furthermore, some of these lesions may express a variable degree of pigmentation. Due to the existence of mucosal melanoma, an accurate diagnosis is paramount. In this narrative review, we focused our attention on management and - in particular- diagnosis of pigmented NMSC (pNMSC) located in the genital region, emphasizing the features assessed by dermoscopy and reflectance confocal microscopy. As an implementation, we included data on pNMSC from the Dermatology Unit of the University of Campania Vanvitelli. BCC in the genital region represents only 1% of all BCC cases. It has been supposed that the mutation of patched 1 may lead to the development of BCC even without concomitant UV exposure. Pigmented variants on genitals have seldom been described. More prominent dermoscopic features seem to be blue-gray ovoid nests and arborizing vessels associated with whitish structureless areas. SCC and Bowen's disease (BD) - a variant of in situ SCC - may be encountered in the genital area and are sometimes associated with human papillomavirus (HPV) infection. Pigmented SCC is very rare, and most of the literature is focused on pigmented BD (pBD), which is mainly characterized by gray-brown dots in a linear fashion and glomerular vessels without evident scales. In conclusion, pNMSC is rarely encountered on genitals; evaluation with dermoscopy or other ancillary devices like RCM is important both to exclude benign lesions like seborrheic keratosis and lentigo and to rule out melanoma., (© 2024 the International Society of Dermatology.)

Purpose: To review the efficacy and safety of oral vismodegib (Erivedge; Genentech) in the management of locally advanced orbital and periorbital basal cell carcinoma (BCC)., Methods: A literature search was conducted last in September 2023 in the PubMed database for English language original research that evaluated the effect of oral vismodegib on orbital and periorbital BCC. Sixty articles were identified and 16 met the inclusion criteria., Results: Most studies demonstrated high response rates, with up to 100% of patients responding to the medication in individual studies and initial complete regression occurring in up to 88% of patients. Vismodegib treatment resulted in significant reductions in tumor volume, resulting in globe preservation for most patients. However, in 12% of patients, the response was partial. Recurrences also occurred with substantial frequency, even after an initial complete response. As such, up to 79.4% of patients required surgical intervention, and up to 23% of patients still required exenteration. Use of these agents resulted in reductions in tumor volume that may delay or prevent the need for exenteration in some, but not all, patients. Importantly, molecular analysis of tissue excised after vismodegib therapy revealed persistent tumor in all patients, with frequent accumulation of mutations that may confer resistance to further hedgehog inhibitor therapy. Although most adverse events were rated as level I or II, side effects were common, with up to 100% of patients in studies experiencing at least 1 event. Muscle cramps, alopecia, weight loss, fatigue, and dysgeusia were the most common adverse events, and several patients discontinued therapy because of them. Furthermore, 1 patient died of sepsis that may have resulted from the therapy., Conclusions: Although level I and II evidence are lacking, most studies indicate a benefit from the use of oral vismodegib to treat orbital and periorbital BCC tumor volume. However, patients should be cautioned about the adverse side effects of treatment and the persistence of tumor cells with mutations that may cause long-term resistance. Use of vismodegib as short-term neoadjuvant therapy may be effective in shrinking tumor volume to reduce surgical morbidity while reducing the frequency and severity of side effects., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Biopsy-based histology has been the foundation of disease diagnosis and management for over a century. A long-sought goal in dermatology is the development of an imaging modality with sufficient resolution and compositional detail to noninvasively interrogate skin histology in vivo. Here, we describe a system that achieves this goal using cross-sectionally scanned, multimodal microscopy (cross-modal). Cross-modal combines multiphoton and reflectance confocal microscopy into one compact system with coordinated three-axis scanning that preserves optical resolution in cross-section. A custom pinhole-free mechanism employing finite-infinite conjugates further simplifies and stabilizes confocal alignment. Evaluated in participants ages 9-81 and Fitzpatrick skin types (FST) 1-5, cross-modal images revealed histological details analogous to those obtained from traditional biopsied tissue. We observed dermal elastosis in sun-damaged skin, elevated melanin in pigmented skin, basaloid nests in basal cell carcinoma, and elongated rete ridges in seborrheic keratosis, supporting cross-modal's potential to deliver histological insights noninvasively., (© 2024. The Author(s).)

Several studies have been published describing development of cutaneous malignancy after vismodegib therapy; no systematic review has been conducted to interpret these data. Our objective was to systemically review reported cases of same-site or different-site cutaneous malignancy after smoothened inhibitor (SMOi) therapy for primary basal cell carcinoma (BCC). PubMed, CINAHL, and Scopus were systematically searched January 1, 2012 - March 28, 2024. Inclusion criteria: primary BCC, SMOi therapy, and biopsy-proven secondary malignancy. Exclusion criteria: non-human subjects. Bias was assessed using Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. Twenty-three cases describing same-site secondary malignancy were included. Average patient age was 67.2 years, mean treatment time 8.4 months, and average latency period to secondary malignancy development of 10.2 months. Five cases describing different-site secondary cutaneous malignancies were included. Mean patient age was 80.4 years, mean treatment time 2.9 months, and mean latency period 4.5 months. Twenty-seven cases were associated with vismodegib, while one case described vismodegib then sonidegib therapy. Pathologies included squamous cell carcinoma, BCC, basosquamous carcinoma, and malignant melanoma. The mechanism(s) by which same-site and different-site secondary malignancy occur are not known; mechanisms may differ depending on location type and secondary tumor type. We discuss multiple mechanistic hypotheses including pharmacologic selective pressure leading to hedgehog pathway mutant cells and activation of pro-growth signaling, and potential protective effect of hedgehog inhibition from melanoma given reports of rapid growth after SMOi discontinuation. This study is limited by the small number of reported cases. Additional research is needed to investigate these hypotheses., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The reflectance confocal microscopy (RCM)-optical coherence tomography (OCT) device has shown utility in detecting and assessing the depth of basal cell carcinoma (BCC) in vivo but is challenging for novices to interpret. Artificial intelligence (AI) applied to RCM-OCT could aid readers. We trained AI models, using OCT rasters of biopsy-confirmed BCC, to detect BCC, create three-dimensional rendering and automatically measure tumour depth. Trained AI models were applied to a separate test set containing rasters of BCC, benign lesions, and healthy skin. Blinded reader analysis and tumour depth correlation with histopathology were conducted. BCC detection improved from viewing OCT rasters only (sensitivity 73.3%, specificity 45.5%) to viewing rasters with AI-generated BCC rendering (sensitivity 86.7%, specificity 48.5%). A Pearson correlation r2 = 0.59 (P = 0.02) was achieved for the tumour depth measurement between AI and histological measured depths. Thus, addition of AI to the RCM-OCT device may expand its utility widely., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Basal cell carcinoma (BCC) is a slowly progressive, locally aggressive and rarely metastasizing cancer, and although its mortality is low, its morbidity and cost of disease are high. While BCC is more common, cutaneous malignant melanoma (CMM) is significant due to its higher mortality rate. These patients can be treated, but recurrence, metastasis and mortality may occur in such patients. Various environmental, phenotypic and genotypic factors, especially ultraviolet (UV) radiations, play a role in the etiology of BCC and CMM. Histopathological examination continues to be the "gold standard" in their diagnosis. Spexin (SPX) and DARS2 are newly discovered proteins linked to many diseases, including cancer. These proteins may have an effect on the development and expression of skin cancers such as BCC and CMM. In this study, we evaluated the potential of SPX and DARS2 expressions as immunohistochemical biomarkers in the differential diagnosis of BCC and CMM. This study was conducted retrospectively using samples taken from the pathology laboratory. A total of 180 patient samples were used. The control group consisted of healthy skin tissues of the patients, and the other groups consisted of BCC and CMM tissues of the same patients. Tissue samples of all three groups were evaluated immunohistochemically with SPX and DARS2. The immunoreactivity of SPX was found to be higher in BCC and CMM tissue samples than in healthy skin tissues in the control group. DARS2 immunoreactivity was found to be higher in CMM tissues compared to the other two groups, and statistically significant in BCC tissues when compared with healthy control group tissues. SPX can be used as an immunohistochemical biomarker in the diagnosis of BCC and CMM. Since DARS2 expression is statistically more significant in CMM tissues than in BCC tissues, it can be used in differential diagnosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Basal cell carcinoma (BCC) is the most frequently diagnosed skin cancer and the most common malignancy in humans. Different morphological subtypes of BCC are associated with a low or high risk of recurrence and aggressiveness, but the underlying biology of how the individual subtypes arise remains largely unknown. As the majority of BCCs appear to arise from mutations in the same pathway, we hypothesized that BCC development, growth and invasive potential is also influenced by the tumour microenvironment and, in particular, by cancer-associated fibroblasts (CAFs) and the factors they secrete., Objectives: To characterize the stroma of the different BCC subtypes with a focus on CAF populations., Methods: To investigate the stromal features of the different BCC subtypes, we used laser capture microdissection (LCM) followed by RNA sequencing (RNA-Seq). Fifteen BCC samples from five different 'pure' subtypes (i.e. superficial, nodular, micronodular, sclerosing and basosquamous; n = 3 each) were selected and included in the analysis. Healthy skin was used as a control (n = 6). The results were confirmed by immunohistochemistry (IHC). We validated our findings in two independent public single-cell RNA-Seq (scRNA-Seq) datasets and by RNAscope., Results: The stroma of the different BCC subtypes were found to have distinct gene expression signatures. Nodular and micronodular appeared to have the most similar signatures, while superficial and sclerosing the most different. By comparing low- and high-risk BCC subtypes, we found that COL10A1 is overexpressed in the stroma of sclerosing/infiltrative and basosquamous but not in micronodular high-risk subtypes. Those findings were confirmed by IHC in 93 different BCC and 13 healthy skin samples. Moreover, scRNA-Seq analysis of BCCs from two independent datasets found that the COL10A1-expressing population of cells is associated with the stroma adjacent to infiltrative BCC and shows extracellular matrix remodelling features., Conclusions: We identified COL10A1 as a marker of high-risk BCC, in particular of the sclerosing/infiltrative and basosquamous subtypes. We demonstrated at the single-cell level that COL10A1 is expressed by a specific CAF population associated with the stroma of infiltrative BCC. This opens up new, tailored treatment options, and suggests COL10A1 as a new prognostic biomarker for BCC progression., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Mohs micrographic surgery (MMS) is a highly effective treatment for skin cancers, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), especially in cosmetically sensitive areas. Despite its high cure rates, the procedure's impact on psychosocial outcomes, influenced by demographic, clinical, psychological, and social factors, necessitates careful consideration. This review aims to identify and synthesize the predictors of psychosocial outcomes following MMS, thereby informing patient management strategies. A comprehensive search of the PubMed database was performed to select peer-reviewed studies in English that discuss these psychosocial aspects in MMS. The review identifies younger age, female gender, smoking, centrally located facial lesions and larger operative defects as factors associated with less favorable psychosocial outcomes. Conversely, patients with strong social support and better preoperative mental health tend to experience more favorable outcomes. This highlights the utility of integrating psychological evaluations and support mechanisms into treatment plans, promoting a patient-centered approach that considers the broader health and psychosocial needs of patients. The implications of this review are significant, suggesting that focusing on these psychosocial determinants allows healthcare providers to improve patient satisfaction and overall well-being., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Keratinocyte carcinoma is the most common form of cancer in the United States. Often treated by surgical excision, electrodessication and curettage, or Mohs surgery, treatment can frequently leave patients with a scar and can be time consuming and inconvenient for both patients and healthcare providers. Utilizing non-ablative fractional laser therapy followed by tirbanibulin ointment, we treated 30 basal and/or squamous cell carcinomas on 23 patients over the age of 50 with varying skin types. Multiple areas of the face and body, and carcinomas at differing stages, were treated. We maximized the depth of penetration of the fractional laser by using bulk heating methods while simultaneously optimizing cosmetic results. This is an ongoing study as we continue to track the progress of our participants. Thus far, no clinical or histological recurrence of carcinoma has been found in any of the treated sites., (© 2024. The Author(s).)

Non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), are increasingly common and present significant healthcare challenges. Neutrophil extracellular traps (NETs), chromatin fibers expulsed by neutrophil granulocytes, can promote immunotherapy resistance via an impairment of CD8 + T cell-mediated cytotoxicity. Here, to identify a potential therapeutic target, we investigate the expulsion of NETs and their relation to CD8 + T cell infiltration in NMSC. Immunofluorescence staining for neutrophils (CD15) and NETs (H3cit), as well as immunohistochemistry for cytotoxic T cells (CD8 + ) on human cSCCs ( n = 24), BCCs ( n = 17) and MCCs ( n = 12), revealed a correlation between neutrophil infiltration and ulceration diameter in BCC and MCC, but not in cSCC. In BCC and cSCC, neutrophil infiltration also correlated with the cross-sectional area (CSA). NETs were not associated with established risk factors but with the presence of an ulceration, and, in cSCC, with abscess-like structures. CD8 + T cell infiltration was not reduced in tumors that were NET-positive nor in those with a denser neutrophil infiltration. This study is the first to report and characterize NETs in NMSC. Thus, it gives an incentive for further research in this relevant yet understudied topic.

Background: Basaloid skin tumors include subtypes of basal cell carcinoma (BCC) and the basaloid variant of squamous cell carcinoma (SCC). Due to their similarity in pathology and clinical presentation, their diagnosis is not straightforward. The aim of this study was to analyze the immunohistochemical expression of HSP105 in basaloid skin tumors, which include BCC, basosquamous carcinoma (BSC), metatypical basal cell carcinoma (MBCC), basaloid squamous cell carcinoma (BSCC), BCC with squamous differentiation as well as conventional SCC., Methods: This retrospective study included 17 cases of BCC, 11 cases of BSC, 8 instances of MBCC, 10 cases of BCC with squamous differentiation, 8 cases of BSCC, and 19 cases of SCC. Their clinical characteristics were summarized, and the paraffin blocks of tumor biopsy specimens were collected for HSP105 immunostaining., Results: In contrast to the BCC group, which stained predominantly negative, SCC stained diffusely positive for HSP105. BSCs showed some areas of HSP105 positivity with a transitional expression signature. HSP105 was only weakly positive in a few cases of MBCC. Although BSCC was stained positive for HSP105, the HSCORE was significantly lower than that of the classic SCC. In BCC with squamous differentiation, focal staining for HSP105 was only seen in the area of squamous differentiation., Conclusion: There was a difference in immunohistochemical staining of HSP105 in basaloid skin tumors which helps in differential diagnosis. Differentiation between BCC, SCC, BSCC, MBCC, and BCC with squamous differentiation can be aided by immunohistochemistry using HSP105., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Nonmelanoma skin cancer (NMSC) is the most prevalent malignancy globally, with basal cell carcinoma (BCC) being the most common type., Aims: This study aims to evaluate the concordance between clinical and pathological diagnoses of BCC, emphasizing the importance of early detection., Methods and Results: In this cross-sectional study, we conducted a retrospective review of clinical and pathological records for 229 patients diagnosed with BCC between 2020 and 2024. The analysis focused on gender, age, lesion location, and diagnostic accuracy. Among the 229 patients, 193 were men (84.3%), and 131 (57.2%) had recorded clinical diagnoses. The mean age of diagnosed patients was 67.72 years. Lesions were primarily located on the scalp (29.5%), face (26.4%), and nose (13.9%). Of the pathological evaluations, 184 cases (80.3%) confirmed BCC, while 45 cases had alternative diagnoses. Notably, 94.6% of clinically diagnosed patients were suspected to have BCC by their physicians. A significant portion of cases (42%) lacked prior clinical diagnoses, reflecting a potential gap in education among nondermatologists regarding BCC recognition., Conclusion: The study found high concordance between clinical and pathological diagnoses of BCC, underscoring the need for improved clinical assessment skills among healthcare providers. Collaboration with dermatologists is essential for accurate diagnosis and improved patient outcomes. Enhanced training in recognizing BCC symptoms is recommended to address the identified gaps in clinical suspicion., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Background: Histopathological analysis represents the gold standard in clinical practice for diagnosing skin neoplasms. While the current diagnostic workflow has specialized in producing robust and accurate results, interpreting tissue architecture and malignant cellular morphology correctly remains one of the greatest challenges for pathologists. This paper aims to explore the prospect of applying x-ray virtual histology to human skin tumor excisions and correlating it with the histological validation., Materials and Methods: Seven skin biopsies containing intriguing melanoma types and pigmented skin lesions were scanned using x-ray Computed micro-Tomography (μCT) and then sectioned for conventional histology assessment., Results: The tissue microarchitecture reconstructed by μCT offers detailed insights into diagnosing the malignancy or benignity of the skin lesions. Three-dimensional reconstruction via x-ray virtual histology reveals infiltrative patterns in basal cell carcinoma and evaluated invasiveness in melanoma. The technology enables the identification of pagetoid distributions of neoplastic cells and the assessment of melanoma depth in three dimensions., Conclusion: Although the proposed approach is not intended to replace conventional histology, the non-destructive nature of the sample and the clarity provided by virtual inspection demonstrate the promising impact of μCT as a valid support method prior to conventional histological sectioning. Indeed, μCT images can suggest the optimal sectioning position before using a microtome, as is commonly performed in histological practice. Moreover, the three-dimensional nature of the proposed approach paves the way for a more accurate assessment of significant prognostic factors in melanoma, such as Breslow thickness, by considering the whole micro-volume rather than a two-dimensional observation., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC) comprise the majority of nonmelanoma skin cancers. Advances have been made in treatment. Sentinel node biopsy should be considered for locally advanced, clinically node-negative cSCCs and MCCs. BCC patients failing traditional surgery and/or radiation are candidates for systemic hedgehog inhibitor therapy. Immune checkpoint inhibitor treatment is available for patients who failed traditional treatment with surgery and/or radiation or who are not candidates for these modalities. Specifically, cemiplimab is approved for advanced BCC; cemiplimab and pembrolizumab for advanced cSCC; and avelumab, pembrolizumab, and retifanlimab-dlwr for recurrent/metastatic MCC., Competing Interests: Disclosure None to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study aims to analyze the literature on periocular basal cell carcinoma, identify research trends, and offer insights into future research areas in this field to assist clinicians and researchers., Methods: 903 publications on periocular basal cell carcinoma were collected from the Web of Science Core Collection database. We assessed the contributions from various countries, institutions, journals, and authors, and performed network analysis using Excel, VOSviewer, and R Studio to represent the prominent areas of research visually., Results: The country with the highest number of publications and citations in this study was the United States of America, with 250 publications, 5917 citations, and the highest H-index of 44. Ophthalmic Plastic and Reconstructive Surgery is the leading journal. The UTMD Anderson Cancer Center had the highest number of publications, accounting for 43, or 4.76% of the total. Selva D from the University of Adelaide, Australia, is the top author with 26 publications, and 751 citations. Targeted therapy for PBCC-related pathways has been a hot topic in recent years., Conclusions: This study using bibliometrics seeks to explore the patterns and focal points of research and analyzes publication patterns, key research areas, influential authors, and prominent journals in periocular basal cell carcinoma during the last 2 decades., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Purpose: Guidelines on clinical margins for basal cell carcinoma (BCC) excisions were recently published, yet the ambiguity regarding the margin continues for surgeons and pathologists. The purpose of this study was to determine the incomplete excision rate of BCC, determine the factors associated with incomplete excision, and evaluate the completeness of reporting between surgeon and pathologist., Methods: A single-center retrospective analysis was conducted on pathology reports from single excisions of BCC specimens between January 1, 2019 to December 31, 2020. The primary outcome was the incomplete excision rate (positive margins) as reported by pathologist. Logistic regression was used to determine the relationship between incomplete excision rate and anatomical location, pathologist, and surgeon. The completeness of surgeon pathology requisition forms was evaluated qualitatively., Results: Seven hundred and fifty-six pathology reports were included. The incomplete excision rate was 12% (n = 94). The most common site of incomplete excision was head and neck (n = 87, 15%), followed by trunk (n = 5, 7%), and extremities (n = 2, 2%). Five hundred and seventy-nine specimens from 6 surgeons and 9 pathologists were included in the logistic regression analysis. The Wald test showed that the location was significantly associated with incomplete excision (p < 0.05), whereas surgeon and pathologist reports were not (p > 0.05). Regarding missing information, only 47 (6%) pathology reports included "excision" in the requisition form. Four hundred and three (53%) specimens had no clinical history., Conclusions: The incomplete excision rate found in this study falls within the report range in the literature. Neither surgeon nor pathologist had significant association with incomplete excision. Incomplete excision rate of BCC may be inflated owing to the lack of standardization in requisition form and pathology reporting., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Excision and histological examination of cutaneous neoplasms are very common diagnostic and therapeutic procedures in dermatological practice. There are often discrepancies between tissue seize in vivo and after histopathological work-up. This may raise questions according to tumor sizes or safety margins., Methods: To investigate the effect of excision and histological processing on the properties of cutaneous neoplasms in real-life 401 specimens in 324 patients were prospectively investigated. Delineated excision margins of cutaneous neoplasms were documented prior to (T0) and post excision (T1). Length, width and thickness were measured after ≥48 h of formalin fixation (T2) and after sectioning (T3) on final histological slices. Accompanying parameters such as patient age, gender, anatomical site, and tumor entity were evaluated., Results: All post-processed tissue exhibited a significant (P<0.001) median (interquartile range) reduction in length, width and thickness of 21.0% (9.5-30.0), 30.7% (20.0-40.0), and 28.0% (4.8-46.7), respectively, irrespective of site, patient age or tumor entity. Maximum median (IQR) reduction for the length and the width was observed right after excision (17.0% [4.3-25.0] and 14.0% [11.1-28.6] reduction). No significant median (IQR) tissue changes between T1 and T2 were observed (length: 4.8% (-4.3-13.3); width: 0% (-17.6-11.1); thickness 0% (-32.0-20.0). Subgroup analyses showed significantly greater tissue shrinkage in younger patients and for tissue sample sites (trunk or lower extremities)., Conclusions: Most relevant shrinkage of cutaneous samples occurs right after excision. Age- and site-depended tissue contractility can influence these effects. Formalin fixation does not affect tissue shrinkage. Smaller tissue sizes on histopathological reports are to be expected.

The Hedgehog (Hh) signaling pathway plays important roles in various physiological functions. Several malignancies, such as basal cell carcinoma (BCC) and medulloblastoma (MB), have been linked to the aberrant activation of Hh signaling. Although therapeutic drugs have been developed to inhibit Hh pathway-dependent cancer growth, drug resistance remains a major obstacle in cancer treatment. Here, we show that the newly identified, 2-{3-[1-(benzylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone analog (LKD1214) exhibits comparable potency to vismodegib in suppressing the Hh pathway activation. LKD1214 represses Smoothened (SMO) activity by blocking its ciliary translocation. Interestingly, we also identified that it has a distinctive binding interface with SMO compared with other SMO-regulating chemicals. Notably, it maintains an inhibitory activity against the Smo D477H mutant, as observed in a patient with vismodegib-resistant BCC. Furthermore, LKD1214 inhibits tumor growth in the mouse model of MB. Collectively, these findings suggest that LKD1214 has the therapeutic potential to overcome drug-resistance in Hh-dependent cancers., (© 2024 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Nonmelanoma skin cancers (NMSCs) are the most common cancers, with high-risk NMSCs sharing features such as poor histologic differentiation, invasion into deeper layers, and anatomic location. NMSC includes basal cell carcinoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma. Herein, the authors describe advances in understanding the genetic mechanisms of malignant transformation and the composition of tumor microenvironment for these cancers. They summarize recent therapeutic advances, including targeted therapy and immunotherapy for NMSCs. Effective skin protection against ultraviolet radiation-induced carcinogenesis remains an urgent unmet need for NMSC prevention. The authors highlight immune-based interventions as novel strategies to address this need., Competing Interests: Disclosure S. Demehri is an inventor on filed patents for the use of calcipotriol plus 5-fluorouracil combination for the treatment of actinic keratosis and T cell-directed HPV vaccine for skin cancer prevention. S. Demehri and T. Oka are inventors on a provisional patent for the development of topical immunotherapy for basal cell carcinoma. T. Lee does not report potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The nose is a common site for the development of skin cancers. Mohs micrographic surgery (MMS) is a highly curative treatment for skin cancer of the nose. Reconstruction of MMS defects on the nose, especially on the distal aspect, can be challenging given the proximity of multiple subunits and limited adjacent tissue reservoirs. Our goal was to describe our experience using a nasal tip rotation flap (NTRF) for MMS defects on the distal nose., Methods: A retrospective review of all MMS cases at multiple institutions between June 2018 and June 2022 was undertaken. Cases that used an NTRF to repair the MMS defect(s) were selected, and data were collected on patient demographics, tumor type, anatomical location of the tumor, preoperative and postoperative size, number of stages needed to clear the tumor, repair dimensions, and any postoperative complications., Results: A total of 66 cases that utilized an NTRF for reconstruction were included. The mean preoperative tumor size was 0.8 cm (range: 0.3-1.6 cm), and the mean defect size was 1.2 cm (range: 0.7-1.9 cm). The defects were most commonly on the nasal tip. There were no significant complications observed., Conclusions: The nasal tip rotation flap is a reliable reconstruction option for MMS defects of the distal nose. This flap can be used for defects that involve the nasal tip, soft triangle, and/or portions of the ala, including the alar rim., (© 2024 The Authors. International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

We present a case of a periocular painless perifolliculitis clinically mimicking basal cell carcinoma (BCC), excised by margin-controlled excision. This case reminds readers that perifolliculitis as a response to rosacea can mimic BCC. The value of diagnostic biopsy and dermoscopy to support management planning and avoid unnecessary surgery is discussed.

Non-melanoma skin cancer (NMSC) is primarily categorized into basal cell carcinoma (BCC), the most prevalent form of skin cancer, and cutaneous squamous cell carcinoma (cSCC), the second most common type. Both BCC and cSCC represent a significant health burden, particularly in immunocompromised individuals and the elderly. The immune system plays a pivotal role in the development and progression of NMSC, making it a critical focus for therapeutic interventions. This review highlights key immunological targets in BCC and cSCC, with a focus on immune checkpoint molecules such as PD-1/PD-L1 and CTLA-4, which regulate T cell activity and contribute to immune evasion. This review also highlights anti-tumor immune cell subsets within the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TILs) and dendritic cells. Additionally, it examines the immunosuppressive elements of the TME, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs), as well as their roles in NMSC progression and resistance to therapy. Emerging strategies targeting these immune elements, such as monoclonal antibodies, are also discussed for their potential to enhance anti-tumor immune responses and improve clinical outcomes. By elucidating the immunological landscape of BCC and cSCC and drawing comparisons to melanoma, this review highlights the transformative potential of immunotherapy in treating these malignancies.

The most common form of primary skin cancer is basal cell carcinoma (BCC). Pigmented BCC is a less common clinical presentation in BCC spectrum, where the tumour contains pigment. Some cases can exhibit morphological features that mimic those of nodular melanoma (NM). We present a woman in her late 40's who had an asymptomatic firm, hyperpigmented nodule on the right cheek resembling pigmented NM. Dermoscopy showed diffuse hyperpigmentation with irregular shiny surface and a solitary haemorrhagic crust. Melanoacanthoma and irritated seborrheic keratosis were the other differentials considered. Punch biopsy showed features of trichoepithelioma initially, subsequent complete excision was suggestive of pigmented BCC.Mortality related to BCC is rare, whereas NM is aggressive. Hence, clinicians need to be aware of this rare presentation of BCC as a hyperpigmented nodule, particularly in dark-skinned individuals. Timely differentiation between melanoma and BCC is crucial given their differing prognosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Giant basal cell carcinoma (GBCC) is a rare and more aggressive variant of basal cell carcinoma. We present a case of GBCC with an overview of the challenges it presents.A man in his 60s presented to the tertiary care unit with a history of an ulcer over the posterior aspect of his left heel for the past 1 year. Examination revealed an ulceroproliferative lesion of 10×8 cm on the posterior aspect of the left heel and lower Tendo-Achilles region. A wedge biopsy of the lesion was performed twice, which demonstrated basal cell carcinoma. The patient underwent excision of the lesion with 10 mm margins. A split-thickness skin graft was placed and secured over the resultant wound with the application of a negative pressure wound dressing.The correlation between tumour size and tumour behaviour is examined. Additionally, the significance of tumour location, width of margins, incidence recurrence or metastasis is also studied., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The establishment of immunotherapy applying immune checkpoint inhibitors (ICI) has provided an important new option for the treatment of solid malignant diseases. However, different tumor entities show dramatically different responses to this therapy. BCC responds worse to anti-PD-1 ICIs as compared to cSCC. Differential immune checkpoint expression could explain this discrepancy and, therefore, the aim of this study was to analyze activating and inhibitory immune checkpoints in cSCC and BCC tissues. Tissue microarrays of the invasive front as well as the tumor core of BCC and cSCC samples were used to evaluate PD-1, PD-L1, CD28, and CD86 expression and their topographic distribution profiles by chromogenic immunohistochemistry. QuPath was used to determine the labeling index. The expression of PD-1, PD-L1, and CD28 was significantly higher in both the tumor core and the invasive front of cSCC samples as compared to BCC ( p < 0.001). In addition, the ratios of PD-L1/CD86 ( p < 0.001) and CD28/CD86 ( p < 0.001) were significantly higher in cSCC. The invasive front of both tumor entities showed higher expression levels of all immune markers compared to the tumor core in both tumor entities. The significantly higher expression of PD-1, PD-L1, and CD28 in cSCC, along with the predominance of the inhibitory ligand PD-L1 as compared to the activating CD86 in cSCC, provide a potential explanation for the better objective response rates to anti-PD-1 immunotherapy as compared to BCC. Furthermore, the predominant site of interaction between the immune system and the tumor was within the invasive front in both tumor types.

Basal cell carcinoma (BCC) is the most frequent malignant tumour worldwide and incidences are rising rapidly. BCC grow locally, but can invade surrounding tissues. Little is known concerning their impact on the health-related quality of life (HrQoL), and limited available data reports contradicting results. Measuring HrQoL in BCC patients should be done using disease-specific questionnaires such as the Basal and Squamous cell carcinoma Quality of Life (BaSQoL) questionnaire. The aim of this study was to assess the BCC-related HrQoL by examining all relevant patient, tumour and treatment characteristics to identify the main factors for the BCC-related impact. Specific attention for older BCC patients wass brought forward because of the often complex decisions in this subgroup. Patients ≥ 18 years with a history of BCC were asked to fill in the BaSQoL questionnaire, consisting of 5 subdomains. Multivariable analyses were done using a generalized additive model (GAM) because of the need for incorporation of non-linear functions. The study obtained approval of the Ethics Committee of the Ghent University Hospital (EC/2019/1352). Informed consent was obtained from all subjects. All experiments were performed in accordance with relevant guidelines and regulations. Four hundred patients with a median age of 66 were enrolled. Mean BaSQoL subscores were 0.78 (SD 0.63) for 'behaviour', 1.01 (SD 0.73) for 'diagnosis&treatment', 0.90 (SD 0.73) for 'worries', 0.40 (SD 0.63) for 'appearance' and 1.20 (SD 0.75) for 'other people', illustrating the low to moderate impact of BCC on the HrQoL. A GAM with subsequent ANOVA testing was done for all relevant variables. In 4 out of 5 BaSQoL subdomains 'age' showed a significant correlation ('behaviour' p = 0.007; 'diagnosis&treatment' p = 0.026; 'worries' p = 0.003; 'appearance' p = 0.008). Lower BaSQoL scores were seen in older patients, meaning less BCC-impact on their HrQoL. There was a clear non-linear correlation between BaSQoL scores and age, illustrating that the impact of BCC on the HrQoL shows a rapid decrease starting around the age of 70. This study is the first to illustrate the relation between the BCC-related HrQoL and the age of patients with the use of a disease-specific HrQoL instrument. We found a lower BaSQoL score in older adults, with a specific age group of interest starting around the age of 70-75. This is an argument for a potential wait-and-see strategy for BCC in these patients., (© 2024. The Author(s).)

Cancer-associated inflammation is a double-edged sword possessing both pro- and anti-tumor properties through ill-defined tumor-immune dynamics. While we previously identified a carcinoma tumor-intrinsic resistance pathway, basal-to-squamous cell carcinoma transition, here, employing a multipronged single-cell and spatial-omics approach, we identify an inflammation and therapy-enriched tumor state we term basal-to-inflammatory transition. Basal-to-inflammatory transition signature correlates with poor overall patient survival in many epithelial tumors. Basal-to-squamous cell carcinoma transition and basal-to-inflammatory transition occur in adjacent but distinct regions of a single tumor: basal-to-squamous cell carcinoma transition arises within the core tumor nodule, while basal-to-inflammatory transition emerges from a specialized inflammatory environment defined by a tumor-associated TREM1 myeloid signature. TREM1 myeloid-derived cytokines IL1 and OSM induce basal-to-inflammatory transition in vitro and in vivo through NF-κB, lowering sensitivity of patient basal cell carcinoma explant tumors to Smoothened inhibitor treatment. This work deepens our knowledge of the heterogeneous local tumor microenvironment and nominates basal-to-inflammatory transition as a drug-resistant but targetable tumor state driven by a specialized inflammatory microenvironment., (© 2024. The Author(s).)

Background: Basal cell carcinoma is the most prevalent skin cancer, most characterized by local aggressiveness but with low metastatic potential, and bone metastasis is quite heterogeneous, thus the incidence profile is variable size from 0.0028% to 0.5%. We have this patient with an unusual example of basal cell carcinoma with bone metastases to add to the scarce report on this matter., Case Description: Here we document a 48-year-old Persian man with a background of being exposed to the sun for a long time. He was diagnosed with an ulcer on the cheek, which was clinically characterized and further confirmed by biopsy as morpheaform basal cell carcinoma. Following the first round of excision, multiple relapses eventually metastasized to the bone. The latter was found on follow-up radiologic scans. This case is characterized by the aggressive nature of the disease and the heterogeneity of basal cell carcinoma growth, thus challenging the conventional view of basal cell carcinoma behavior. Treatment included surgical excision of the primary lesion, which was treated with radiotherapy afterward. However, the skeleton improved slowly during follow-up, and palliative care was eventually pursued to control symptoms and improve quality of life., Conclusions: This was a rare case of basal cell carcinoma metastasis to non-bone organs, which reminded us to consider basal cell carcinoma metastasis, especially in the case of atypical basal cell carcinoma. Therefore, risk-aware patient management is essential. Moreover, these findings highlight the role of further research into the mechanisms of basal cell carcinoma metastasis, leading to improved therapeutic strategies that may lead to potential improvements in patient outcomes., (© 2024. The Author(s).)

Better mechanistic understanding of desmosome disruption and acantholysis in Grover's disease (GD) may improve management of this disease. Recent molecular studies highlighted promising pathways to be explored by directly comparing GD and selected features of associated skin diseases. The association between GD and cutaneous keratinocyte carcinomas, the most prevalent non-melanoma skin cancers (NMSC), is not completely characterized. To review the medical literature regarding GD-associated cutaneous keratinocyte cancers, focusing on molecular features, pathophysiological mechanisms, and disease associations, to help guide future research and patient management. GD has been associated with a variety of skin conditions, but its association with skin cancers has been rarely reported. Between 1983 and 2024, only nine scientific papers presented data supporting this association. Interestingly, we found that GD may mimic multiple NMSCs, as few authors reported GD cases misdiagnosed as multiple cutaneous squamous cell carcinomas for more than 4 years or the presence of superficial basal cell carcinoma-like areas associated with focal acantholysis. In conclusion: (a) GD may be an imitator of multiple NMSCs, and (b) the relationship between GD and NMSCs may reveal promising pathways for the mechanistic understanding of desmosome disruption and acantholysis in GD and may even lead to its reclassification as a distinctive syndrome.

Line-field confocal optical coherence tomography (LC-OCT) is a new technology for skin cancer diagnostics. However, the interobserver agreement (IOA) of known image markers of keratinocyte carcinomas (KC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), as well as precursors, SCC in situ (CIS) and actinic keratosis (AK), remains unexplored. This study determined IOA on the presence or absence of 10 key LC-OCT image markers of KC and precursors, among evaluators new to LC-OCT with different levels of dermatologic imaging experience. Secondly, the frequency and association between reported image markers and lesion types, was determined. Six evaluators blinded to histopathologic diagnoses, assessed 75 LC-OCT images of KC (21 SCC; 21 BCC), CIS (12), and AK (21). For each image, evaluators independently reported the presence or absence of 10 predefined key image markers of KCs and precursors described in an LC-OCT literature review. Evaluators were stratified by experience-level as experienced (3) or novices (3) based on previous OCT and reflectance confocal microscopy usage. IOA was tested for all groups, using Conger's kappa coefficient (κ). The frequency of reported image marker and their association with lesion-types, were calculated as proportions and odds ratios (OR), respectively. Overall IOA was highest for the image markers lobules (κ = 0.68, 95% confidence interval (CI) 0.57;0.78) and clefting (κ = 0.63, CI 0.52;0.74), typically seen in BCC (94%;OR 143.2 and 158.7, respectively, p < 0.001), followed by severe dysplasia (κ = 0.42, CI 0.31;0.53), observed primarily in CIS (79%;OR 7.1, p < 0.001). The remaining seven image-markers had lower IOA (κ = 0.06-0.32) and were more evenly observed across lesion types. The lowest IOA was noted for a well-defined (κ = 0.07, CI 0;0.15) and interrupted dermal-epidermal junction (DEJ) (κ = 0.06, CI -0.002;0.13). IOA was higher for all image markers among experienced evaluators versus novices. This study shows varying IOA for 10 key image markers of KC and precursors in LC-OCT images among evaluators new to the technology. IOA was highest for the assessments of lobules, clefting, and severe dysplasia while lowest for the assessment of the DEJ integrity., (© 2024. The Author(s).)

Lipids interfere with absorbance measurements conducted using colorimetric methods. To monitor lipemia, some systems measure absorbance using an analyzer. This report describes a novel case of interference with the lipemia index without lipemia. A 64-year-old woman with giant basal cell carcinoma underwent resection and sentinel lymph node biopsy. The patient had been subcutaneously injected with patent blue during sentinel lymph node resection. After surgery, her serum and urine were yellow-green, and the lipemia index, calculated by measuring absorbance at 658 nm (main wavelength) and 694 nm (secondary wavelength) using a JCA-BM8040 chemistry analyzer, was high. The absorbance spectrum of the patient's serum and patent blue solution were compared to determine the cause of the high lipemia index. The patient's serum and the patent blue solution showed absorption at wavelengths between 540 and 698 nm. Moreover, the absorbance was concentration-dependent for patent blue. These results thus indicated that the patient's serum contained patent blue. Here, we report a case wherein patent blue affected the lipemia index. Thus, it must be noted that patent blue injection may yield inaccurate results when evaluating lipemia index., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Keratinocyte cancer (KC) in Australia poses a unique healthcare challenge due to its high prevalence and the requirement for multidisciplinary management of many cases. Advances in radiation therapy (RT) have increased its use in treating different keratinocyte cancer presentations. Understanding the indications for RT and the role that general practitioners (GPs) play in the treatment pathway are imperative to ensure best patient outcomes., Objective: This review examined the efficacy, advances and treatment considerations of RT for the management of keratinocyte cancer, and role of the GP in the treatment pathway., Discussion: Radiation therapy offers effective alternatives to, or adjuvants for, surgery in existing keratinocyte cancer treatments in appropriate cases. The evolving RT landscape necessitates GPs to be well informed for effective case identification, referral and management. This includes understanding RT advances, protocols, treatment reactions and managing patient expectations. Continuing education in this space is important for GPs to understand the suitability of RT for their patients.

Surgical excision is the most effective treatment of skin carcinomas (basal cell carcinoma or squamous cell carcinoma). Preoperative assessment of tumoral margins plays a decisive role for a successful result. The aim of this work was to evaluate the possibility that hyperspectral imaging could become a valuable tool in solving this problem. Hyperspectral images of 11 histologically diagnosed carcinomas (six basal cell carcinomas and five squamous cell carcinomas) were acquired prior clinical evaluation and surgical excision. The hyperspectral data were then analyzed using a newly developed method for delineating skin cancer tumor margins. This proposed method is based on a segmentation process of the hyperspectral images into regions with similar spectral and spatial features, followed by a machine learning-based data classification process resulting in the generation of classification maps illustrating tumor margins. The Spectral Angle Mapper classifier was used in the data classification process using approximately 37% of the segments as the training sample, the rest being used for testing. The receiver operating characteristic was used as the method for evaluating the performance of the proposed method and the area under the curve as a metric. The results revealed that the performance of the method was very good, with median AUC values of 0.8014 for SCCs, 0.8924 for BCCs, and 0.8930 for normal skin. With AUC values above 0.89 for all types of tissue, the method was considered to have performed very well. In conclusion, hyperspectral imaging can become an objective aid in the preoperative evaluation of carcinoma margins., (© 2024. The Author(s).)

Abstract: Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n = 35), and control tissues were subjected to immunohistochemical analysis for the activation of mTOR pathway, and immunohistochemical staining intensity was evaluated by a dermatopathologist. BCCs (compared with normal skin) had elevated levels of eIF4EBP1 ( Padjusted = 0.0336), which is downstream of mTOR. a serine/threonine kinase Phospho-(AKT), which interacts with mTOR, was also significantly elevated (perinuclear: Padjusted < 0.0001; cytoplasmic: Padjusted = 0.0021). When off-label topical 1% sirolimus was used on a pediatric patient with GS, we noted reduction of new BCC development and decreased size of existing neoplasms clinically suspicious for BCCs. This treatment was well tolerated after 2 years of continuous use, with no other treatments needed during this period. Topical sirolimus is a promising therapeutic candidate against both sporadic and GS-associated BCC. Multicenter, prospective studies are needed to understand the efficacy and safety of topical mTOR inhibitors in BCC treatment, and ascertain whether the immunohistochemical markers downstream of mTOR could have predictive value in identifying BCCs most likely to respond to topical mTOR inhibitors, such as sirolimus., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hedgehog pathway inhibitors (HHIs) have broadened the treatment options available for patients with advanced basal cell carcinoma (BCC) for whom traditional therapeutic approaches are not feasible or effective. Sonidegib and vismodegib are oral HHIs that were approved for treatment of patients with advanced BCC after demonstrating promising efficacy in the pivotal Phase II BOLT (NCT01327053) and ERIVANCE (NCT00833417) trials, respectively. However, the incidence and types of treatment-emergent adverse events (AEs) observed with these agents may limit continuous use of HHIs and ultimately impact clinical outcomes. In this review, we summarize the safety and tolerability profiles of sonidegib and vismodegib and discuss potential management strategies for HHI class-effect AEs, including muscle spasms, creatine phosphokinase increase, alopecia, and dysgeusia. These AEs primarily occur early in treatment and can lead to treatment discontinuation. Differences in the pharmacokinetic profiles of sonidegib and vismodegib may contribute to the variability noted in times to onset and resolution of these and other AEs. Evidence suggests that protocol modifications, such as treatment interruptions and dose reductions, are effective ways to manage AEs while maintaining disease control. Nonpharmacologic and pharmacologic interventions may also be considered as part of an AE management strategy. Overall, healthcare providers and patients with advanced BCC should be aware of the HHI class-effect AEs and plan effective management strategies to avoid treatment discontinuation and optimize therapeutic response., (© 2024. The Author(s).)

Skin tumors are the most common tumors in humans and the clinical characteristics of three common non-melanoma tumors (IDN, SK, BCC) are similar, resulting in a high misdiagnosis rate. The accurate differential diagnosis of these tumors needs to be judged based on pathological images. However, a shortage of experienced dermatological pathologists leads to bias in the diagnostic accuracy of these skin tumors in China. In this paper, we establish a skin pathological image dataset, SPMLD, for three non-melanoma to achieve automatic and accurate intelligent identification for them. Meanwhile, we propose a lesion-area-based enhanced classification network with the KLS module and an attention module. Specifically, we first collect thousands of H&E-stained tissue sections from patients with clinically and pathologically confirmed IDN, SK, and BCC from a single-center hospital. Then, we scan them to construct a pathological image dataset of these three skin tumors. Furthermore, we mark the complete lesion area of the entire pathology image to better learn the pathologist's diagnosis process. In addition, we applied the proposed network for lesion classification prediction on the SPMLD dataset. Finally, we conduct a series of experiments to demonstrate that this annotation and our network can effectively improve the classification results of various networks. The source dataset and code are available at https://github.com/efss24/SPMLD.git., Competing Interests: Declaration of competing interest The authors do not have any possible conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Merkel cell polyomavirus (MCPyV), a human polyomavirus that is unequivocally linked to merkel cell carcinoma (MCC), has been found in association with keratinocytes carcinomas (KC), especially basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Nevertheless, there is scarce information about the possible involvement of MCPyV in the development of KC., Objectives: To assess the presence of MCPyV DNA and Large-T Antigen (LT-Ag) via Polymerase Chain Reaction (PCR) and Immunohistochemistry (IHC) in cases of KC, and to correlate its presence with immunohistochemical markers p16, p53, and ki67, tumor type and subtype, sun-exposed location, and epidemiological data., Methods: The prevalence of MCPyV DNA, LT-Ag, and immunohistochemical markers p16, p53, and ki67 was assessed by PCR and Immunohistochemistry (IHC) in 127 cases of KC, these results were correlated with tumor type and subtype, sun-exposed location, and epidemiological data., Results: The MCPyV DNA was detected in 42.57% (43 of 101) cases by PCR, the LT-Ag was detected in 16.4% (20 of 122) of cases, p16 in 81.5% (97 of 119), p53 in 66.4% (83 of 125), ki67 in 89% (73 of 82). No correlation between MCPyV LT-Ag and DNA confronted with tumor type, subtype, location site, and immunohistochemical markers was found. A single correlation between the MCPyV LT-Ag and cSCC tumors and peri-tumoral lymphocyte cells was noted., Study Limitations: Further steps need to be taken to better evaluate the MCPyV influence and its possible role in KC carcinogenesis, as the evaluation of the virus genome state, the gene sequence that encodes LT-Ag in the KC tumor cells, and in situ hybridization for viral DNA or RNA in these cells., Conclusions: Despite the frequent detection of MCPyV in KC, the data available so far does not support the hypothesis of a causal relationship between them., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Background and Objective: The prevalence of extensive skin cancers increases with the aging of the population. Surgical management is the gold standard of curative treatment while morbidity is not negligible. There are few data in the literature concerning extensive head and neck cutaneous cancers. The aim of this article is to report our experience of curative management of head and neck extensive skin cancers., Method: In this single-center retrospective observational study, we report a series of 17 patients with extensive skin facial cancers treated by surgery between 2013 and 2022 in the maxillofacial surgery department of the Pitié-Salpêtrière Hospital. We collected clinical, therapeutic, histological, and carcinologic data., Results: The median age of the patients was 66 years [35-94]. There were 9 male and 8 women. Scalp (39 %) and cheek (22 %) locations were the most frequent ones. The most frequent histological types were squamous cell carcinoma (61 %) and basal cell carcinoma (17 %). Three patients received neoadjuvant treatment. The surgical treatment consisted mainly of carcinological resection followed by one-stage reconstruction by free flap for 5 (30 %) patients and without reconstruction for primary for 12 (70 %) patients, of whom 8 benefited from secondary reconstruction. Five patients received adjuvant radiotherapy or radio-chemotherapy. With a median follow-up of 40 months (2-72), the median overall survival was 40 months (12-72)., Conclusion: We know that extensive skin cancers of the face have a good prognosis on condition that the carcinological and reconstructive requirements are respected. Surgery remains the cornerstone of treatment while the improvement of adjuvant therapies, in particular the rise of immunotherapies or other targeted therapies, may allow to limit recurrences., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Competing Interests: Declaration of conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose of Review: This review provides an update on approved and emerging systemic therapies in the treatment of locally advanced or metastatic non-melanoma skin cancers (squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma)., Recent Findings: Many studies demonstrate the effectiveness of immunotherapy for all types of non-melanoma skin cancer. For basal cell carcinoma (BCC), hedgehog inhibitors (HHI) remain first-line but with poor tolerability. Numerous clinical trials studying both neoadjuvant and adjuvant use of anti-PD-1 and anti-PD-L1 therapies in advanced NMSC are under investigation. There is a growing number of systemic therapies available to treat non-melanoma skin cancers. The advent of immunotherapy has revolutionized the field and greatly improved survival compared to historical survival rates with cytotoxic chemotherapy., (© 2024. The Author(s).)

Background: One of the hereditary syndromes associated with multiple early-onset basal cell carcinomas (BCCs) is basal cell nevus syndrome (BCNS), of which a minority is caused by germline SUFU mutations. Germline SUFU mutations show a spectrum of phenotypes, of which multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC) is one. Patients with MHIBCC develop multiple basaloid skin tumors from middle age onwards., Methods: Three patients presenting with an MHIBCC phenotype were tested for a germline SUFU mutation. Skin biopsies were assessed by two dermatopathologists., Results: Our study adds three new pathogenic SUFU variants, including a mosaic, to the current literature. Literature suggests a spectrum of phenotypes of patients carrying the same SUFU mutation, which ranges from the MHIBCC phenotype, to BCNS, to patients that develop life-threatening brain tumors. This last risk is significantly higher in germline SUFU mutation carriers when compared to BCNS patients carrying germline PTCH1 mutations., Conclusions: Germline SUFU mutation carriers should be recognized as a distinct group of patients carrying specific health risks, independent of meeting the BCNS criteria. Phenotypic prediction based on the specific SUFU mutation seems unfeasible. It is of utmost importance that the less apparent MHIBCC phenotype is recognized, to provide (second generation) germline SUFU mutation carriers appropriate healthcare., (© 2024 The Author(s). Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)