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Simple Summary: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with the head and neck region being the most common location. Perineural invasion (PNI), or the invasion of cancer into and around nerves, is a high-risk factor in cSCC associated with poor outcomes. The mechanisms of PNI in cSCC are poorly understood, but recent studies suggest that cross-communication between nerve components and cancer is a contributing factor. A better understanding of the mechanisms that promote PNI may lead to new therapies that improve outcomes in cSCC patients. Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a lifetime risk of 14–20% that is rising every year. Although prognosis for cSCC is generally good, certain high-risk features of cSCC portend increased rates of nodal and distant metastasis, recurrence, and disease-specific mortality. One such high-risk factor is perineural invasion (PNI), which is broadly defined as the invasion of cancer into and around nerves. Compared to other high-risk factors, PNI presence is associated with the highest risk for locoregional and distant metastasis. Still, the mechanisms underlying the pathogenesis of PNI remain poorly understood. Recent studies suggest the migration and invasion of tumors into nerves is a result of complex molecular crosstalk within the tumor-nerve microenvironment, wherein the milieu of signaling molecules simultaneously promote neuronal growth and tumor cell invasion. Methods: Understanding the molecular and cellular mechanisms that promote PNI will lead to future developments of targeted therapies that may improve locoregional control and survival. Results/Conclusions: In our article, we aim to provide a comprehensive review of recent findings about the pathogenesis of PNI, clinical implications of PNI-positive disease in cSCC, available treatment modalities, and potential future therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: The most frequent initial site of metastasis for patients with melanoma is the regional lymph node basin. Management of regional lymph nodes was transformed through the development of lymphatic mapping and sentinel lymph node biopsy. Through a series of prospective multicenter clinical trials, the role of sentinel lymph node biopsy has been established and clarified. Although areas of controversy remain, the procedure now has a well-defined role in treatment and holds promise as a source of valuable information to guide our understanding of melanoma biology and treatment into the future. Starting with its earliest descriptions, melanoma has been recognized as a tumor with a predilection for metastasis to regional lymph nodes. This tendency led to initial recommendations for very aggressive early surgical management of the regional nodal basin. However, those recommendations were the source of much controversy over nearly a century, until the minimally invasive surgical technique of sentinel lymph node (SLN) biopsy was developed by Morton, Cochran and colleagues. This technique has been evaluated in a series of prospective clinical trials, which have clarified its role and the management of lymph nodes in this disease. Current controversies relating to SLN biopsy include optimal selection of patients for the procedure, the role of gene expression profiling in initial melanoma management, and the potential therapeutic effects of SLN biopsy-based management. In addition, the SLN appears to be a rich source of data relating to the host–tumor interface and the immune microenvironment, which may advance our understanding of the biology of melanoma. Finally, although the surgical technique is well developed at this point, there may be additional technical improvements that are possible as well. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with skin lesions suspicious for skin cancer or atypical melanocytic nevi of uncertain malignant potential often present to dermatologists, who may have variable dermoscopy triage clinical experience. We evaluated the clinical utility of a digital dermoscopy image-based artificial intelligence algorithm (DDI-AI device) on the diagnosis and management of skin cancers. Thirty-six United States board-certified dermatologists evaluated 50 cases with clinical images and DDI of the same skin lesions (25 malignant and 25 benign), first without and then with knowledge of the DDI-AI device output. We identified that when using the DDI-AI device, management sensitivity, management specificity, diagnostic sensitivity, and diagnostic specificity all increased over baseline use of clinical images and dermoscopy images. Hence, the use of the DDI-AI device may quickly, safely, and effectively improve dermoscopy performance, skin cancer diagnosis, and management when used by dermatologists, independent of training and experience. Background: Patients with skin lesions suspicious for skin cancer or atypical melanocytic nevi of uncertain malignant potential often present to dermatologists, who may have variable dermoscopy triage clinical experience. Objective: To evaluate the clinical utility of a digital dermoscopy image-based artificial intelligence algorithm (DDI-AI device) on the diagnosis and management of skin cancers by dermatologists. Methods: Thirty-six United States board-certified dermatologists evaluated 50 clinical images and 50 digital dermoscopy images of the same skin lesions (25 malignant and 25 benign), first without and then with knowledge of the DDI-AI device output. Participants indicated whether they thought the lesion was likely benign (unremarkable) or malignant (suspicious). Results: The management sensitivity of dermatologists using the DDI-AI device was 91.1%, compared to 84.3% with DDI, and 70.0% with clinical images. The management specificity was 71.0%, compared to 68.4% and 64.9%, respectively. The diagnostic sensitivity of dermatologists using the DDI-AI device was 86.1%, compared to 78.8% with DDI, and 63.4% with clinical images. Diagnostic specificity using the DDI-AI device increased to 80.7%, compared to 75.9% and 73.6%, respectively. Conclusion: The use of the DDI-AI device may quickly, safely, and effectively improve dermoscopy performance, skin cancer diagnosis, and management when used by dermatologists, independent of training and experience. [ABSTRACT FROM AUTHOR]

Simple Summary: This case series study evaluates the use of reflectance confocal microscopy (RCM) for assessing treatment outcomes after superficial radiation therapy (SRT) in managing localized non-melanoma skin cancer (NMSC). Conducted between March 2020 and December 2023, this study included 29 patients with 38 lesions. Following RCM diagnosis, the patients underwent SRT, and outcomes were assessed at six months using RCM and clinical evaluation. The results showed 100% tumor clearance with no residual activity observed upon conducting follow-up RCM. Clinically, scarring and mild erythema were observed, with moderate to severe inflammation in six lesions. While the generalizability of the results of our study is limited by the size of the study population, our findings suggest that RCM and SRT may be effective in managing localized NMSC non-invasively, potentially offering an alternative to traditional surgical methods, particularly for elderly or surgically unsuitable patients. Background: Traditional treatment methods for non-melanoma skin cancer (NMSC) include surgical excision with histological evaluation, yet advancements such as reflectance confocal microscopy (RCM) and superficial radiation therapy (SRT) offer non-invasive management alternatives. This study aims to evaluate the use of RCM for the evaluation of treatment outcomes after SRT in managing localized NMSC. Methods: A prospective interventional case series study was conducted on patients treated for NMSC with SRT between March 2020 and December 2023. Suspected NMSC lesions were initially evaluated with a handheld dermoscope and then imaged at multiple depths using a VivaScope 1500 RCM. Two dermatologists trained in RCM reviewed the images. Confirmed NMSC lesions were biopsied and treated with SRT, followed by RCM imaging at six months post-treatment to assess cancer clearance, scarring, and inflammation. Results: Of the 38 lesions (composed of SCC (24) and BCC (14)) treated affecting the 29 patients, all lesions showed no residual tumor activity upon conducting follow-up RCM (100% clearance). Scarring and mild erythema were noted clinically. Six lesions demonstrated moderate to severe inflammation at a 6-month follow-up. Conclusions: This study demonstrates successful non-invasive management of localized NMSC using RCM and SRT. RCM was able to non-invasively demonstrate complete tumor clearance achieved by SRT with minimal adverse effects. These findings support considering the use of RCM and SRT as primary diagnostic, monitoring, and treatment options for NMSC without the need for biopsies, especially for elderly patients or those unsuitable for surgery due to medical conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: Animal models are crucial for exploration of the causes of and potential treatments for squamous cell carcinoma, a common type of skin cancer. This study compared four different hairless mouse models to determine which is most suitable for studying skin cancer development when exposed to ultraviolet (UV) light. The models varied in their skin characteristics, such as the presence of melanin, cholesterol level, and immune system function. By monitoring various skin health parameters and analyzing proteasome activity, this study found that the SKH-hr2+ApoE and SKH-hr2 models were the most effective for further research into squamous cell carcinoma. In contrast, the SKH-hr1 model, despite its common use, was less suitable. These findings will help guide future research efforts in understanding and developing treatments for skin cancer. Background: In recent decades, a significant global increase in the incidence of non-melanoma skin cancer has been observed. To explore the pathogenesis of and potential therapeutic approaches for squamous cell carcinoma, various in vivo studies using mouse models have been conducted. However, investigations comparing different hairless mouse models, with or without melanin, as well as models with hypercholesterolemia and immunosuppression, in terms of their ability to induce squamous cell carcinoma have yet to be undertaken. Methods: Four mouse strains, namely SKH-hr1, SKH-hr2, SKH-hr2+ApoE, and immunodeficient Nude (Foxn1 knockout), were exposed to UVA and UVB radiation three times per week, initially to 1 Minimal Erythemal Dose (MED), incrementally increased weekly to a maximum dose of 3 MED. Clinical evaluation, photodocumentation, and biophysical parameters were monitored, along with proteasome protein activity and histopathological assessments. Results: The SKH-hr1 model primarily developed actinic keratosis without significant progression to invasive squamous cell carcinoma (SCC), while the SKH-hr2 and SKH-hr2+ApoE models exhibited a higher likelihood and intensity of papilloma and aggressive SCC formation, with the latter showing upregulated proteasome activity. Histopathological analysis confirmed the presence of poorly differentiated, invasive SCCs in the SKH-hr2 and SKH-hr2+ApoE models, contrasting with the less aggressive SCCs in the Nude mice and the mixed lesions observed in the SKH-hr1 mice. Conclusions: The SKH-hr2+ApoE and SKH-hr2 mice were identified as the most suitable for further exploration of squamous cell carcinogenesis. In contrast, the SKH-hr1 mice were found to be the least suitable, even though they are albino. Notably, proteasome analysis revealed a potential role of proteasome activity in squamous cell carcinogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin cancer is a major global problem, and over the last decade, ultrasound technology has advanced significantly, enhancing our ability to detect and identify the most common types of skin cancer, including both the primary tumor and its locoregional metastases. Background: Skin cancer is the most common cancer in human beings. Ultrasound is a powerful and non-invasive imaging technique that has expanded its use in dermatology, including in the skin cancer field. The full range of critical anatomical information provided by ultrasound cannot be deduced from a naked eye examination, palpation, or other imaging techniques such as dermoscopy, confocal microscopy, magnetic resonance imaging, or PET-CT (Positron Emission Tomography-Computed Tomography). Methods: This review practically analyzes the main ultrasonographic features of the most common types of skin cancers and the performance of the locoregional staging according to the literature, which is illustrated by state-of-the-art clinical and ultrasonographic correlations. Results: The most common types of skin cancer show recognizable ultrasonographic patterns. Conclusions: Among the current radiological imaging techniques, ultrasound has the highest axial spatial resolution. Compared to other imaging techniques used in dermatology, it shows the great advantage of penetrating the soft tissues thoroughly, which allows us to detect and identify the most common skin types of skin cancer, including both the primary tumor and its locoregional metastases. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous melanoma (CM) is an aggressive skin cancer that develops from melanocytic cells. The most important prognostic factor is still the vertical tumour thickness according to Breslow. Liver function is associated with better overall patient outcomes and is currently under increasing investigation in cancer patients. Current findings show that liver function is an important factor in different tumour entities and represents a potential biomarker. Therefore, we aimed to evaluate liver metabolism by using liver scores in CM. High tumour thickness (≥1.66 mm) and aspartate transaminase-to-platelet ratio index (APRI ≥ 0.2241) at the initial diagnosis were associated with a worse prognosis in stage I and II melanoma. Background: Neoadjuvant and adjuvant therapies are currently getting increasingly important in cutaneous melanoma (CM) management. However, there is still a lack of prognostic tools to identify which patients have a poor prognosis. There is increasing evidence that the liver score may be a potential prognostic parameter in different tumour types. The aim was to investigate whether established liver scores can establish the prognosis of CM. Methods: According to established methods, the APRI, the MELD score, the MELD-Na score and the De Ritis ratio were calculated from the laboratory values at the time of the initial diagnosis. Survival was compared with the Kaplan–Meier curve and tested with log-rank tests. Risk factors associated with cutaneous melanoma-specific survival (CMSS) and progression-free survival (PFS) were assessed by using the Cox proportional hazards regression model. To determine the diagnostic accuracy, we performed a time-dependent ROC analysis. Results: A total of 423 patients were included, including 141 patients in AJCC stage (2017) I (33.3%), 82 in stage II (19.4%), 128 in stage III (30.3%) and 72 in stage IV (17%). Median time until melanoma-specific death was 99 months (IQR: 37–126). In addition, 37.6% of patients relapsed with a median time to relapse of 88 months (IQR: 17.5–126). In all stages, tumour thickness and ulceration were independent markers for predicting CMSS and PFS (p < 0.05). The multivariable analysis with all stages showed no significant association with CM outcome for liver scores (p > 0.05). The subgroup analysis revealed that the APRI (≥0.2241) was associated with CMSS and PFS in melanoma stages I and II, independently of tumour thickness, age and ulceration (HR 2.57, 95% CI 1.14–5.75; HR 2.94, 95% CI 1.42–6.09, respectively). Conclusions: The 20-year prognosis of AJCC stage I and II CM was dependent on tumour thickness and the APRI. High tumour thickness and an APRI ≥ 0.2241 at the initial diagnosis were associated with a worse prognosis. Future studies should investigate the independent prognostic value of the APRI in low-stage CM. Furthermore, the APRI score could be a potential biomarker for nomograms. [ABSTRACT FROM AUTHOR]

Simple Summary: This research explored a new method to evaluate surgical margins when removing non-melanoma skin cancer, aiming to reduce the time patients need to stay in the hospital. Typically, surgeons use 3D histology to ensure all cancer tissues have been removed, but this process is time-consuming. This study suggests using ex vivo reflectance confocal microscopy (evRCM), which allows for quicker margin assessments. While evRCM showed high accuracy in confirming cancer-free areas, it was not as effective in detecting small remaining cancer cells as histology. Despite this limitation, evRCM significantly reduced patients' time in the hospital. These findings suggest that evRCM could become a valuable tool for improving the speed and accuracy of skin cancer surgery; however, its effectiveness is limited. Close collaboration between surgeons and pathologists is mandatory to achieve good patient outcomes. Background/Objectives: To ensure that non-melanoma skin cancer (NMSC) is completely removed in healthy tissue, micrographically controlled surgery (3D histology) is often performed, which can prolong the inpatient stay. This study examined ex vivo reflectance confocal microscopy (evRCM) for perioperative assessment of surgical margins, specifically in cases where re-excision was necessary due to incomplete removal of cutaneous tumor tissue. Methods: NMSC re-excisions were evaluated using evRCM by a cutaneous surgeon, with retrospective review by an independent pathologist when results differed from histology. Results: evRCM demonstrated high specificity (0.96; 95% CI, 0.90–0.99) but low sensitivity (0.20; 95% CI, 0.06–0.51). Unlike pathology, which discards outer surgical margins, evRCM examined the true surgical margins. Retrospective pathology analysis of the misdiagnosed cases confirmed that 25% (n = 2/8) were false negative and 75% (n = 6/8) were potentially false positive, resulting in a sensitivity of 0.2–0.8. Notably, evRCM led to a 113-day reduction in in-hospital stays, probably resulting in increased patient satisfaction and cost-effectiveness. Conclusions: evRCM was valuable for speeding up the assessment of surgical margins in patients with re-excised NMSC. Proper tissue preparation and assessment require interdisciplinary collaboration between cutaneous surgeons, pathologists, and physician assistants, emphasizing the need for standardized operating procedures. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to evaluate the efficacy of radiotherapy for skin lesions in classic Kaposi's sarcoma. A retrospective analysis was performed. Response after radiotherapy was defined as follows: Complete response indicated no clinically detectable skin lesions and no symptoms. Partial response was defined as a reduction in lesion height by more than half or a lighter lesion color compared to before treatment. In-field recurrence was defined as the appearance of new lesions within a previously irradiated field. The overall response rate was 100%. The efficacy of radiotherapy was evident, even in cases involving disseminated lesions. Further research on the optimal dose and fractionation is deemed necessary. Objectives: Classic Kaposi's sarcoma (CKS) is a rare malignancy with diverse clinical presentations, lacking a standard treatment. While localized therapies are commonly used for symptomatic lesions, radiotherapy (RT) has demonstrated effectiveness. This study aims to evaluate the efficacy of RT for treating skin lesions in CKS. Methods: A retrospective analysis was conducted on patients with KS treated between April 2012 and January 2024. In total, 69 lesions in 16 patients were included. Treatment response was defined as follows: complete response (CR) indicated the absence of clinically detectable skin lesions and symptoms; partial response (PR) was a reduction in lesion height by more than half or a lighter lesion color compared to before treatment. In-field recurrence was the appearance of new lesions within a previously irradiated field. Logistic regression analysis was used to investigate factors influencing response and in-field recurrence. Results: The median follow-up period was 52 months (range, 3–138 months). The overall response rate was 100%, with 92.8% of the patients achieving CR and 7.2% receiving PR. PR was observed in three patients with five lesions, all of which remained stable. In-field recurrence occurred in two patients with initially advanced disease, and all recurrent lesions responded to RT. No variables were significantly associated with response or in-field recurrence. Conclusions: RT for CKS showed a 100% response rate, with complete symptom relief in all cases. The effectiveness of RT was evident, even in cases involving disseminated lesions. Further research is needed to determine the optimal RT dose and fractionation. [ABSTRACT FROM AUTHOR]

Simple Summary: Outgrowth of skin tumors in cancer patients who receive therapies with BRAF inhibitors is frequently observed as an undesired side effect. Infection with certain human papillomaviruses may play a role in BRAF-inhibitor-associated skin tumor development. In this study, the impact of BRAF inhibitors and Ultraviolet B (UVB) light on tumor growth was investigated in laboratory mice after infection of their skin with a murine papillomavirus. We could show that the combination of BRAF inhibitor treatment and UVB exposure resulted in higher numbers of virus-induced tumors compared with virus-infected mice that had received only BRAF inhibitors, only UVB irradiation or no additional treatment. This shows that BRAF inhibitors, particularly when combined with UVB light, support skin tumor growth in mice and may represent a novel way by which BRAF inhibitors contribute to skin cancer development. The development of keratinocytic skin tumors, presumably attributable to paradoxical activation of the MAPK pathway, represents a relevant side effect of targeted therapies with BRAF inhibitors (BRAFis). The role of cutaneous papillomavirus infection in BRAFi-associated skin carcinogenesis, however, is still inconclusive. Employing the Mus musculus papillomavirus 1 (MmuPV1) skin infection model, the impact of BRAFis and UVB exposure on papillomavirus induced skin tumorigenesis was investigated in immunocompetent FVB/NCrl mice. Systemic BRAF inhibition in combination with UVB light induced skin tumors in 62% of the MmuPV1-infected animals. In contrast, significantly fewer tumors were observed in the absence of either BRAF inhibition, UVB irradiation or virus infection, as demonstrated by lesional outgrowth in 20%, 5% and 0% of the mice, respectively. Combinatory exposure to BRAFis and UVB favored productive viral infection, which was shown by high numbers of MmuPV1 genome copies and E1^E4 spliced transcripts and an abundance of E6/E7 oncogene mRNA and viral capsid proteins. BRAF inhibition, but not viral infection or UVB light, activated ERK1/2, whereas γH2AX expression, inducible by UVB light, remained unaltered by BRAFis. These results provide experimental evidence that BRAF inhibition and UVB irradiation synergistically promote MmuPV1-induced skin tumor development in vivo. This indicates an alternative pathway by which papillomavirus skin infection may contribute to BRAFi-associated skin tumorigenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma (cSCC) is a common and potentially dangerous skin cancer, especially for people with weakened immune systems, like those who have had organ transplants or certain blood cancers. These individuals are up to 100 times more likely to develop cSCC compared with the general population. This review discusses the current treatments for cSCC in these high-risk patients, emphasizing the importance of prevention and the variety of treatment options available. Using high-SPF sunscreen and certain medications can help reduce the chances of developing cSCC. Adjusting the medications that suppress the immune system can also lower the risk. Surgery remains the main treatment, with radiation therapy recommended for more serious cases. Other treatments such as chemotherapy and newer targeted therapies have been used, with mixed results. Immunotherapy, which helps the body's own immune system fight the cancer, shows promise but needs more research to ensure it is safe for these vulnerable patients. This study highlights the need for future research to explore personalized treatment plans and combination therapies to improve outcomes for people with weakened immune systems. Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and poses a significant risk to immunosuppressed patients, such as solid organ transplant recipients and those with hematopoietic malignancies, who are up to 100 times more likely to develop cSCC compared with the general population. This review summarizes the current state of treatment for cSCC in immunosuppressed patients, focusing on prevention, prophylaxis, surgical and non-surgical treatments, and emerging therapies. Preventative measures, including high-SPF sunscreen and prophylactic retinoids, are crucial for reducing cSCC incidence in these patients. Adjusting immunosuppressive regimens, particularly favoring mTOR inhibitors over calcineurin inhibitors, has been shown to lower cSCC risk. Surgical excision and Mohs micrographic surgery remain the primary treatments, with adjuvant radiation therapy recommended for high-risk cases. Traditional chemotherapy and targeted therapies like EGFR inhibitors have been utilized, though their efficacy varies. Immunotherapy, particularly with agents like cemiplimab and pembrolizumab, has shown promise, but its use in immunosuppressed patients requires further investigation due to potential risks of organ rejection and exacerbation of underlying conditions. Treatment of cSCC in immunosuppressed patients is multifaceted, involving preventive strategies, tailored surgical approaches, and cautious use of systemic therapies. While immunotherapy has emerged as a promising option, its application in immunosuppressed populations necessitates further research to optimize safety and efficacy. Future studies should focus on the integration of personalized medicine and combination therapies to improve outcomes for this vulnerable patient group. [ABSTRACT FROM AUTHOR]

A cutaneous carcinosarcoma (cCS) is a rare and aggressive skin cancer characterized by both carcinomatous (epithelial) and sarcomatous (mesenchymal) components, making it a biphasic tumor. Despite its occurrence in various organs, a cCS is exceptionally rare in the skin, predominantly affecting older males. The etiology of a cCS is unclear, but it may originate from a single progenitor cell capable of dual differentiation or from a collision of carcinoma and sarcoma cells. Clinically, a cCS presents as a rapidly growing, painful, ulcerated nodule or plaque on sun-exposed skin, with a high risk of local invasion and metastasis. Histopathologically, a cCS includes various epithelial components, such as squamous cell carcinoma and basal cell carcinoma, along with undifferentiated sarcomatous components resembling atypical fibroxanthoma. The tumor may also exhibit heterologous differentiation like angiosarcomatous or rhabdomyosarcomatous features. We present three cases of a cCS, highlighting their clinical and histological characteristics and comparing them with previously reported cases. Understanding a cCS is complicated by its rarity and diverse presentation, emphasizing the need for further research to elucidate its pathogenesis and optimal management. [ABSTRACT FROM AUTHOR]

Digital papillary adenocarcinoma (DPA) is a rare malignant neoplasm which arises from the sweat glands and has metastatic potential. DPA exhibits a wide range of architectural features and exhibits low-grade to high-grade features, so distinguishing DPA from benign skin neoplasms, including acral hidradenoma, poses significant diagnostic challenges. The recent literature suggests a strong association between DPA and human papillomavirus (HPV) 42, a low-risk HPV (LR-HPV) subtype, and a possible association between DPA and BRAF p.V600E. To explore these associations, we assessed the utility of in situ hybridization (ISH) for LR-HPV (types 6, 11, 40, 42, 43, 44) and immunohistochemistry (IHC) for BRAF p.V600E in diagnosing DPA and distinguishing DPA from acral hidradenoma. With institutional review board approval, we retrospectively identified 15 specimens of DPA (from 13 patients) and 3 cases of acral hidradenoma. Of the 13 DPA cases, 6 were negative for LR-HPV and BRAF p.V600E; 6 were positive for only LR-HPV; and 1 was positive for only BRAF p.V600E but negative for LR-HPV. All three cases of acral hidradenoma were negative for LR-HPV and BRAF p.V600E. As our sample size is limited, larger studies are needed to assess the value of detecting LR-HPV and BRAF p.V600E in the distinction of DPA and acral hidradenoma. However, our findings indicate a stronger association of DPA with LR-HPV than with BRAF p.V600E. [ABSTRACT FROM AUTHOR]

Simple Summary: The scarcity of specific clinical and dermoscopic criteria makes solitary pink skin lesions the most challenging to diagnose. Cherry angioma, clear cell acanthoma, dermal nevus, keloid, hypertrophic scar, and Spitz nevus are the most common benign lesions that share similar clinical and dermoscopic features. Furthermore, some malignant lesions, such as basal cell carcinoma, actinic keratosis, or amelanotic melanoma, can be indistinguishable from the above-mentioned benign pinkish lesions. Several studies have demonstrated the excellent diagnostic accuracy of reflectance confocal microscopy in increasing sensitivity and specificity compared to dermoscopy alone for the diagnosis of skin cancer. This study aimed to summarize the application of dermoscopy and RCM for the differential diagnosis of benign and malignant pinkish–reddish skin lesions, although, in suspicious lesions, the final diagnosis should always be confirmed after surgical excision and histopathological evaluation. Diagnosing solitary pink skin lesions poses a significant challenge due to the scarcity of specific clinical and dermoscopic criteria. Several benign lesions, such as cherry angioma, clear cell acanthoma, dermal nevus, keloid, hypertrophic scar, and Spitz nevus, often exhibit similar clinical and dermoscopic features. This similarity extends to some malignant lesions, including basal cell carcinoma, actinic keratosis, and amelanotic melanoma, making differentiation difficult. Recent studies highlight the enhanced diagnostic accuracy of reflectance confocal microscopy (RCM), which offers increased sensitivity and specificity compared to dermoscopy alone for diagnosing skin cancer. This study aims to summarize the application of dermoscopy and RCM in distinguishing between benign and malignant pinkish–reddish skin lesions. The integration of RCM with traditional dermoscopic techniques improves the ability to accurately identify and differentiate these lesions. However, it is crucial to note that for any suspicious lesions, a final diagnosis must be confirmed through surgical excision and histopathological evaluation. This comprehensive approach ensures accurate diagnosis and appropriate treatment, highlighting the importance of combining advanced imaging techniques in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma is among the most frequent cutaneous tumors. Over the years, the understanding and diagnostic sensitivity has increased due to the introduction and improved knowledge of dermoscopy, as well as of more recent noninvasive technologies, such as reflectance confocal microscopy and line-field confocal optical coherence. Imaging plays a central role in the staging of the disease; however, its role in the follow-up, as well as the choice of the best technique in each patient, is still not fully clarified. Cutaneous squamous cell carcinoma (SCC) is the second most frequent skin cancer, accounting for approximately 20% of all cutaneous malignancies, and with an increasing incidence due to the progressive increment of the average age of life. The diagnosis is usually firstly suspected based on clinical manifestations; however, dermoscopic features may improve diagnostic sensitivity in cases of an uncertain diagnosis and may guide the biopsy, which should be performed to histopathologically prove the tumor. New diagnostic strategies may improve the sensitivity of the cutaneous SCC, such as reflectance confocal microscopy and line-field confocal optical coherence, for which increasing data have been recently published. Imaging has a central role in the staging of the diseases, while its exact role, as well as the choice of the best techniques, during the follow-up are not fully clarified. The aim of this literature review is to describe diagnostic clinical and instrumental tools of cutaneous SCC, with an insight into the role of imaging in the diagnosis and follow-up of cutaneous SCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin cancer rates in Canada are rising quickly, with about one-third of Canadians likely to be affected in their lifetime. Despite this alarming trend, government actions to reduce skin cancer are limited. Our study, conducted in Manitoba, found that many residents have risky sun exposure habits and lack awareness about skin cancer. Over 65% reported a history of sunburns, more than half had used tanning beds, and a large majority recently tanned for pleasure. Misconceptions are common, with over 50% believing that tans are healthy or a sign of beauty. Moreover, sun protection practices are inadequate, with less than 60% using protective clothing and under 50% using sunscreen. These findings highlight the need for targeted public health campaigns to improve awareness and promote better sun protection behaviors to prevent future skin cancers in Manitoba. The rapidly increasing skin cancer rates in Canada are alarming, with current data estimating that 1/3 of Canadians will be affected in their lifetime. Thus, deeper understanding of high-risk sun exposure behaviors is needed to help counter this trend. Only limited action has been taken by federal/provincial governments to reduce skin cancer incidence. A cross-sectional survey study was conducted in Manitoba, with frequency counts, means, and percentages used to encapsulate responses. Age- and gender-adjusted odds ratios were calculated using logistic regression analyses. Our study identified worrying inadequacies in sun protective behaviors and attitudes, with the threat of such high-risk behaviors amplified by a lack of skin cancer awareness. Alarming elements were noted in participants' sun exposure history (>65% reported a history of sunburns, >50% previously used a tanning bed, and >75% recently tanned for pleasure), beliefs and attitudes (>50% believe that they look better/healthier with a tan, and >40% believe that having a base tan is protective against further sun damage), and sun protection efforts (sun protective clothing was used <60% of the time, sunscreen was used by <50%, and there was a lack of knowledge about sunscreen characteristics in ~30% of respondents), in addition to significant differences being established between demographic subgroups (based on gender, age, skin phototype, income, and education attained). This study provides worrisome insight onto the grim landscape of sun protective behaviors and attitudes in Manitoba, which will inevitably translate into higher skin cancer rates and should serve as a call to action to promote targeted public health messaging in this jurisdiction and beyond. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients who have undergone solid-organ transplant are at higher risk of developing aggressive cutaneous squamous cell carcinoma (CSCC), which is associated with increased morbidity and mortality. There has been a major shift in the management landscape of locally advanced and metastatic CSCC with the introduction of immunotherapy. Despite this, the management of patients with a history of immunosuppression including solid-organ transplant recipients (SOTRs) remains challenging due to safety and efficacy concerns. This review addresses the unique aspects of biology and clinical care of this patient population and highlights recent advances. The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Early detection of melanoma and differentiation from benign nevi can be challenging even for the most experienced dermatologists. To improve melanoma detection, artificial intelligence algorithms incorporating dermoscopy have been developed, but lack transparency and therefore have limited training value for healthcare providers. To address this, an automated approach utilizing imaging biomarker cues (IBCs), logical features extracted from images that mimic expert dermatologists' dermoscopic pattern recognition skills, was developed. This study excluded deep learning approaches to which IBCs are complementary or alternative. Ten participants assessed 78 dermoscopic images (39 melanomas and 39 nevi) first without IBCs and then with IBCs. Using IBCs significantly improved diagnostic accuracy: sensitivity increased significantly from 73.69% to 81.57% (p = 0.0051) and specificity increased from 60.50% to 67.25% (p = 0.059). These results indicate that incorporating IBCs can significantly enhance melanoma diagnosis, with potential implications for improved screening practices. Further research is needed to confirm these findings across a variety of healthcare providers. Incorporation of dermoscopy and artificial intelligence (AI) is improving healthcare professionals' ability to diagnose melanoma earlier, but these algorithms often suffer from a "black box" issue, where decision-making processes are not transparent, limiting their utility for training healthcare providers. To address this, an automated approach for generating melanoma imaging biomarker cues (IBCs), which mimics the screening cues used by expert dermoscopists, was developed. This study created a one-minute learning environment where dermatologists adopted a sensory cue integration algorithm to combine a single IBC with a risk score built on many IBCs, then immediately tested their performance in differentiating melanoma from benign nevi. Ten participants evaluated 78 dermoscopic images, comprised of 39 melanomas and 39 nevi, first without IBCs and then with IBCs. Participants classified each image as melanoma or nevus in both experimental conditions, enabling direct comparative analysis through paired data. With IBCs, average sensitivity improved significantly from 73.69% to 81.57% (p = 0.0051), and the average specificity improved from 60.50% to 67.25% (p = 0.059) for the diagnosis of melanoma. The index of discriminability (d′) increased significantly by 0.47 (p = 0.002). Therefore, the incorporation of IBCs can significantly improve physicians' sensitivity in melanoma diagnosis. While more research is needed to validate this approach across other healthcare providers, its use may positively impact melanoma screening practices. [ABSTRACT FROM AUTHOR]

Background/Objectives: Lentigo maligna (LM) and lentigo maligna melanoma (LMM) are significant subtypes of melanoma, with an annual incidence of 1.37 per 100,000 people in the U.S. These skin tumors, often found in photo-exposed areas such as the face, are frequently misdiagnosed, leading to delayed treatment or unnecessary excisions, especially in the elderly. Facial melanocytic skin tumors (lentigo maligna—LM/lentigo maligna melanoma—LMM) and their simulators (solar lentigo, pigmented actinic keratosis, seborrheic keratosis and lichen planus-like keratosis) often affect the periocular region. Thus, their diagnosis and management can involve different medical figures, mainly dermatologists and ophthalmologists. This study aimed to evaluate the ability of ophthalmologists to diagnose and manage pigmented skin lesions of the periorbital area. Methods: A multicentric, retrospective, cross-sectional study on a dataset of 79 periorbital pigmented skin lesions with both clinical and dermoscopic images was selected. The images were reviewed by six ophthalmologists and two dermatologists. Descriptive statistics were carried out, and the accuracy, sensitivity, and specificity, with their 95% confidence interval (95% CI), were estimated. Results: Ophthalmologists achieved a diagnostic accuracy of 63.50% (95% CI: 58.99–67.85%), while dermatologists achieved 66.50% (95% CI: 58.5–73.8). The sensitivity was lower for ophthalmologists in respect to dermatologists, 33.3% vs. 46.9%, respectively. Concerning the case difficulty rating, ophthalmologists rated as "difficult" 84% of cases, while for dermatologists, it was about 30%. Management was also consistently different, with a "biopsy" decision being suggested in 25.5% of malignant lesions by ophthalmologists compared with 50% of dermatologists. Conclusions: Ophthalmologists revealed a good diagnostic potential in the identification of periorbital LMs/LMMs. Given progressive population ageing and the parallel increase in facial/periorbital skin tumors, the opportunity to train new generations of ophthalmologists in the early diagnosis of these neoformations should be considered in the next future, also taking into account the surgical difficulty/complexity of this peculiar facial area. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma (cSCC) is a complex disease arising from an interplay of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. While most cSCC cases can be treated with surgery, metastatic and locally advanced forms have a significantly worse prognosis and limited treatment options. The high mutational burden in cSCC makes it challenging to identify true driver alterations. Beyond genetics, the tumor microenvironment and its interaction with the immune system play a critical role in cSCC progression, evidenced by differences observed between immunocompromised and immunocompetent patients. In recent years, new therapeutic approaches have emerged, including immunotherapy and EGFR inhibitors, which have shown efficacy in treating advanced cSCC. Understanding the underlying mechanisms driving cSCC is crucial for developing novel and more effective therapies. This review aims to provide a comprehensive overview of the mutational landscape and microenvironmental factors in cSCC. Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes difficult to differentiate. Despite this, several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR. In addition to mutations, the tumor microenvironment and the manipulation and evasion of the immune system play a critical role in cSCC progression. Novel therapeutic approaches, such as immunotherapy and EGFR inhibitors, have been used to target these dysregulations, and have shown promise in treating advanced cSCC cases, emphasizing the need for targeted interventions considering both genetic and microenvironmental factors for improved patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma (cSCC) of the head and neck, although treatable, can be highly aggressive. Certain pathological features of cSCC can drastically impact prognosis. Therefore, the presence of a few such features is considered in both staging and treating cSCC. In this review, we summarize the current literature regarding pathological prognostic indicators of cSCC, including depth of invasion, surgical margins, perineural invasion, lymphovascular invasion, extranodal extension, tumor grade, tumor subtype, premalignant lesions, and molecular markers. Furthermore, we characterize the impact of each indicator on clinical outcomes of head and neck cSCC, their role in dictating adjuvant therapy for this tumor, and their incorporation or lack thereof into current staging and treatment guidelines. Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers worldwide, with an incidence that has increased over the past 30 years. Although usually curable with excision, cSCC can become widely metastatic and aggressive with poor outcomes. Whereas the clinical and radiographic extent of any cancer will always guide selection of treatment modality, pathological features of cSCC also play an important role in determining prognosis and, subsequently, the need for further therapy. Therefore, reviewing and summarizing the current literature regarding pathological prognostic indicators of cSCC is essential to improving clinical outcomes. The present literature review yielded depth of invasion, surgical margins, perineural invasion, extranodal extension, lymphovascular invasion, tumor grade, tumor subtype, premalignant lesions, and molecular markers as key prognostic indicators, all with varying recommendations for adjuvant therapy. Notably, some of these factors have not been incorporated into either the American Joint Committee on Cancer staging system (8th edition) or National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for cSCC. This review highlights a need for further research into these prognostic indicators and their role in determining the need for adjuvant treatment in head and neck cSCC. [ABSTRACT FROM AUTHOR]

Background: Line-field confocal optical coherence tomography is a novel technology able to reproduce a "virtual biopsy" of the skin. The aim of this review is to explore the application of line-field confocal optical coherence tomography (LC-OCT) in various skin diseases, covering skin cancers, inflammatory and infectious skin diseases, genetic diseases, cosmetic procedures, and less common disorders. Methods: Study selection was conducted based on LC-OCT and using pertinent MeSh terms, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines from inception to March 2024; to evaluate the quality and risk of bias of studies, Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used. Results: the search retrieved 154 papers according to the selection criteria; after removing publications by one or more of the exclusion criteria, a total of 96 studies were found to be suitable for the analysis. Conclusions: Increasing evidence supports the use of LC-OCT as an adjunctive diagnostic tool for the in vivo diagnosis of a variety of skin tumors. As this device can be considered a "bridge" between dermoscopy and histopathology, widening applications in numerous fields of clinical dermatology, including inflammatory skin disease treatment, presurgical mapping, cosmetic procedures, and monitoring of non-invasive therapies, have been explored. [ABSTRACT FROM AUTHOR]

The primary aim of this study was to evaluate the activation of the PERP and Akt oncogenes in the induction of skin cancer in FVB/N mice by a stepwise chemical process. Forty four-week-old female FVB/N mice were randomly divided into a control group (n = 8) and two experimental groups (group A: n = 16, group B: n = 16). In the study, the groups were subjected to a two-stage carcinogenesis procedure. This consisted of an initial application of 97.4 nmol DMBA to shaved skin on the back, followed by applications of 32.4 nmol TPA after thirteen weeks for group A and after twenty weeks for group B. The control group received no treatment. Skin conditions were monitored weekly for tumor development. At the end of the experiment, the animals were euthanized for further tissue sampling. Examination of the skin lesions in the experimental groups showed a correlation with tumor progression, ranging from dysplasia to carcinoma. Tumor samples were examined both histologically and immunohistochemically. Notably, and PERP expression was higher in precancerous than in malignant tumors. The differences in expression between precancerous and benign tumors provide further evidence of a role for PERP and Akt in the transition from benign to malignant states. Our findings underscore the critical roles of PERP and Akt in the pathogenesis of skin cancer and suggest their potential as biomarkers for early detection and targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma and basal cell carcinoma are the most common cancers worldwide and surgical excision is the first-line treatment. Brachytherapy, which delivers a high dose of radiation to tumor tissue while sparing healthy tissue, represents a curative and conservative alternative in certain situations, particularly in elderly patients. Since the withdrawal of iridium wires from the market, brachytherapy has mainly been performed with high-dose-rate iridium-192 (HDR). Few studies and recommendations exist on HDR brachytherapy. Our study aims to evaluate the efficacy of HDR brachytherapy in terms of local control, survival, toxicity, and quality of life in patients with facial periorificial cutaneous squamous cell carcinoma or basal cell carcinoma treated in our center between 2015 and 2021. While treatment of localized cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) is based on surgery, brachytherapy, which delivers a high dose of radiation to tumor tissue while sparing healthy tissue, is an alternative. Since the withdrawal of iridium wires from the market, brachytherapy has mainly been performed with high-dose-rate iridium-192 (HDR). This study evaluated the efficacy of HDR brachytherapy in terms of local control, survival, toxicity, and quality of life in patients with facial periorificial cutaneous SCC or BCC treated in our center between 2015 and 2021. Sixty-seven patients were treated for SCC (n = 49) or BCC (n = 18), on the nose (n = 29), lip (n = 28), eyelid (n = 7), or ear (n = 3). The majority had Tis or T1 tumors (73.1%). After a median follow-up of 28 months, 8 patients had a local recurrence. The local control rate at 3 years was 87.05% (95% CI 74.6–93.7). All patients developed grade 1–2 acute radio-mucositis or radiodermatitis and one experienced reversible grade 3 acute radio-mucositis. Of the 27 patients who completed the quality-of-life questionnaire, 77.8% recommended the treatment. This study confirms that HDR brachytherapy for facial cutaneous carcinomas provides good local control, good tolerance, and satisfactory functional outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma, a severe type of skin cancer, often becomes resistant to chemotherapy, making it difficult to treat. This research investigates a novel mechanism by which growth hormone (GH) contributes to chemotherapy resistance. We examined small particles, called exosomes, which are released from melanoma cells treated with GH and found to carry proteins that increase drug resistance and cancer cell movement. The effects were more pronounced when GH was combined with the chemotherapy drug, doxorubicin. We also found that blocking the GH action with a drug called pegvisomant reduced the expression of these exosomal proteins, ultimately making the cancer cells more responsive to chemotherapy and less likely to migrate. Our findings provide new insights into how GH action promotes melanoma chemoresistance via exosomes, suggesting that targeting/inhibiting GH action could improve melanoma treatment. Drug resistance in melanoma is a major hindrance in cancer therapy. Growth hormone (GH) plays a pivotal role in contributing to the resistance to chemotherapy. Knocking down or blocking the GH receptor has been shown to sensitize the tumor cells to chemotherapy. Extensive studies have demonstrated that exosomes, a subset of extracellular vesicles, play an important role in drug resistance by transferring key factors to sensitize cancer cells to chemotherapy. In this study, we explore how GH modulates exosomal cargoes from melanoma cells and their role in drug resistance. We treated the melanoma cells with GH, doxorubicin, and the GHR antagonist, pegvisomant, and analyzed the exosomes released. Additionally, we administered these exosomes to the recipient cells. The GH-treated melanoma cells released exosomes with elevated levels of ABC transporters (ABCC1 and ABCB1), N-cadherin, and MMP2, enhancing drug resistance and migration in the recipient cells. GHR antagonism reduced these exosomal levels, restoring drug sensitivity and attenuating migration. Overall, our findings highlight a novel role of GH in modulating exosomal cargoes that drive chemoresistance and metastasis in melanoma. This understanding provides insights into the mechanisms of GH in melanoma chemoresistance and suggests GHR antagonism as a potential therapy to overcome chemoresistance in melanoma treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Detecting key areas in tissue samples is crucial for accurate and timely cancer diagnosis. This study focuses on using advanced deep learning techniques to analyze images of skin tumors, specifically melanoma and nevi. By training our deep learning-based model on a dataset of these images, we aimed to detect key areas in each image and simultaneously classify whether a given image shows melanoma or a benign nevus. Our method achieved an accuracy of 92.3% in classifying the images from a test set, meaning it correctly identified most cases. This approach not only helps in distinguishing between these types of skin tumors but also shows promise for broader applications in diagnosing various cancers, potentially improving clinical outcomes and reducing healthcare costs. Automated region of interest detection in histopathological image analysis is a challenging and important topic with tremendous potential impact on clinical practice. The deep learning methods used in computational pathology may help us to reduce costs and increase the speed and accuracy of cancer diagnosis. We started with the UNC Melanocytic Tumor Dataset cohort which contains 160 hematoxylin and eosin whole slide images of primary melanoma (86) and nevi (74). We randomly assigned 80% (134) as a training set and built an in-house deep learning method to allow for classification, at the slide level, of nevi and melanoma. The proposed method performed well on the other 20% (26) test dataset; the accuracy of the slide classification task was 92.3% and our model also performed well in terms of predicting the region of interest annotated by the pathologists, showing excellent performance of our model on melanocytic skin tumors. Even though we tested the experiments on a skin tumor dataset, our work could also be extended to other medical image detection problems to benefit the clinical evaluation and diagnosis of different tumors. [ABSTRACT FROM AUTHOR]

Nuclear Protein in Testis (NUT)-rearranged tumors comprise predominantly NUT carcinoma but also include certain lymphomas, leukemias, skin appendage tumors, and sarcomas. Although histologically diverse, all are genetically identified by oncogenic rearrangement in the NUTM1 gene. Many fusion partners occur, and NSD3 is NUT carcinoma's third most common partner. Herein, we present a case of a 26-year-old man with an NSD3::NUTM1 fusion sarcoma. The patient presented at the age of 13 months with a scalp nodule. Over the next 24 years, he experienced five local recurrences and ultimately expired of a rapidly progressive recurrence. His treatment included surgical resections, radiation, and various chemotherapies. Deceptively, the clinical presentation and histopathology aligned with a malignant peripheral nerve sheath tumor, a diagnosis rendered at initial resection with concurrence by a national soft tissue tumor expert. The patient's exceptionally long survival could be due to NSD3 as the fusion partner, aided by the initial small tumor size and young patient age. Thus, this case expands NUT fusion sarcomas' histologic and immunohistochemical profile to include mimicking a malignant peripheral nerve sheath tumor (MPNST). Additionally, it indicates that the NSD3::NUTM1 fusion can drive sarcoma genesis. [ABSTRACT FROM AUTHOR]

Simple Summary: This research investigates the use of teledermoscopy, a method that involves patients using a smartphone dermatoscope attachment to take pictures of skin lesions for remote evaluation by dermatologists. This approach aims to reduce the need for in-person visits for skin cancer screening and triage. This study found that incorporating smartphone dermatoscope images significantly reduced the number of lesions requiring in-person evaluation compared to clinical images alone. This suggests that patient-led teledermoscopy could decrease unnecessary visits for benign lesions, potentially improving access to dermatology consultations for patients with suspicious or malignant lesions. Overall, this research highlights a promising strategy to enhance skin cancer detection and streamline healthcare delivery in dermatology through telemedicine. Introduction: Teledermatology, defined as the use of remote imaging technologies to provide dermatologic healthcare services to individuals in a distant setting, has grown considerably in popularity since its widespread implementation during the COVID-19 pandemic. Teledermoscopy employs a smartphone dermatoscope attachment paired with a smartphone camera to visualize colors and microstructures within the epidermis and superficial dermis that cannot be seen with the naked eye ABCD criteria alone. Methods: Our retrospective observational cohort and case–control study evaluated the utility of loaning a smartphone dermatoscope attachment to patients for remote triage of self-selected lesions of concern for skin cancer. The primary outcome was the number (percentage) of in-person follow-up visits required for patients who submitted lesion images, either with or without accompanying dermoscopic images. A medical record review was conducted on all Oregon Health & Science University Department of Dermatology spot check image submissions utilizing the smartphone dermatoscopes between August 2020 and August 2022. De-identified dermoscopic images of lesions that included corresponding non-dermoscopic clinical images in their submission (n = 70) were independently reviewed by a blinded expert dermoscopist. The expert used standard clinical algorithms (ABCD criteria for clinical images; dermoscopy three-point checklist for dermoscopic images) to determine whether the imaged lesion should be converted to an in-person visit for further evaluation and consideration for biopsy. Results: Of the 70 lesions submitted with corresponding clinical and dermoscopy images, 60 met the criteria for in-person evaluation from clinical (non-dermoscopic) image review compared to 28 meeting the criteria for in-person evaluation from dermoscopic images of the same lesion. Thus, a 53% reduction in conversion to an in-person consultation with the addition of smartphone dermatoscope images in virtual lesion triage was observed (p < 0.001, McNemar's Test). Conclusion: Implementing patient-led teledermoscopy may reduce the frequency of in-person visits for benign lesions and consequently improve access to in-person dermatology consultations for patients with concerning and possibly malignant lesions. [ABSTRACT FROM AUTHOR]

A line-field confocal optical coherence tomography (LC-OCT) combines confocal microscopy and optical coherence tomography into a single, rapid, easy-to-use device. This meta-analysis was performed to determine the reliability of LC-OCT for diagnosing malignant skin tumors. PubMed, EMBASE, Web of Science databases, and the Cochrane Library were searched for research studies in the English language from inception till December 2023. To assess quality and the risk of bias, the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used. The sensitivity and specificity of each study were calculated. The bivariate summary sensitivity and specificity were calculated using the linear mixed model. Five studies with 904 reported per lesion analyses in our study; the specificity and sensitivity ranged from 67% to 97% and 72% to 92%, respectively. The pooled specificity and sensitivity were 91% (95% CI: 76–97%) and 86.9% (95% CI: 81.8–90.8%), respectively. The summary sensitivity and specificity from the bivariate approach are 86.9% (95% CI: 81.8–90.8%) and 91.1% (95% CI: 76.7–97.0%), respectively. The area under the curve is 0.914. LC-OCT shows great sensitivity and specificity in diagnosing malignant skin tumors. However, due to the limited number of studies included in our meta-analysis, it is premature to elucidate the true potential of LC-OCT. [ABSTRACT FROM AUTHOR]

Cancer remains a significant global health concern, with increasing genetic and metabolic irregularities linked to its onset. Among various forms of cancer, skin cancer, including squamous cell carcinoma, basal cell carcinoma, and melanoma, is on the rise worldwide, often triggered by ultraviolet (UV) radiation. The propensity of skin cancer to metastasize highlights the importance of early detection for successful treatment. This narrative review explores the evolving role of artificial intelligence (AI) in diagnosing head and neck skin cancers from both radiological and pathological perspectives. In the past two decades, AI has made remarkable progress in skin cancer research, driven by advances in computational capabilities, digitalization of medical images, and radiomics data. AI has shown significant promise in image-based diagnosis across various medical domains. In dermatology, AI has played a pivotal role in refining diagnostic and treatment strategies, including genomic risk assessment. This technology offers substantial potential to aid primary clinicians in improving patient outcomes. Studies have demonstrated AI's effectiveness in identifying skin lesions, categorizing them, and assessing their malignancy, contributing to earlier interventions and better prognosis. The rising incidence and mortality rates of skin cancer, coupled with the high cost of treatment, emphasize the need for early diagnosis. Further research and integration of AI into clinical practice are warranted to maximize its benefits in skin cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

The detrimental effects of ultraviolet radiation (UVR) on human skin are well-documented, encompassing DNA damage, oxidative stress, and an increased risk of carcinogenesis. Conventional photoprotective measures predominantly rely on filters, which scatter or absorb UV radiation, yet fail to address the cellular damage incurred post-exposure. To fill this gap, antioxidant molecules and DNA–repair enzymes have been extensively researched, offering a paradigm shift towards active photoprotection capable of both preventing and reversing UV–induced damage. In the current review, we focused on "active photoprotection", assessing the state-of-the-art, latest advancements and scientific data from clinical trials and in vivo models concerning the use of DNA-repair enzymes and naturally occurring antioxidant molecules. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (cSCC) is a common and increasingly prevalent form of skin cancer, posing significant health challenges. Understanding the molecular mechanisms involved in cSCC progression is crucial for developing effective treatments. The primary aim of this research was to evaluate the activation of NOTCH1 and FGFR2 oncogenes in inducing skin cancer in FVB/N mice through a stepwise chemical process. Forty female FVB/N mice, aged four weeks, were randomly divided into a control group (n = 8) and two experimental groups (group A: n = 16, group B: n = 16). This study involved subjecting the groups to a two-stage carcinogenesis procedure. This included an initial application of 97.4 nmol DMBA on shaved skin on their backs, followed by applications of 32.4 nmol TPA after thirteen weeks for group A and after twenty weeks for group B. The control group did not receive any treatment. Their skin conditions were monitored weekly to detect tumor development. After the experiment, the animals were euthanized for further tissue sampling. The examination of skin lesions in the experimental groups showed a correlation with tumor progression, ranging from dysplasia to carcinoma. Tumor samples were assessed both histologically and immunohistochemically. Notably, FGFR2 expression was higher in benign, precancerous, and malignant tumors compared to normal tissue. NOTCH1 expression was only elevated in benign tumors compared to normal tissue. This study demonstrates a clear correlation of FGFR2 expression and the progression of cutaneous neoplasms, while NOTCH 1 expression is inversely correlated in FVB/N mice. This suggests an early involvement of these oncogenes in the development of skin tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper addresses the complex diagnostic challenges of pigmented lesions in the oral mucosa, ranging from benign to potentially malignant conditions. Our study provides a narrative review with a clinical case overview to guide clinicians in differentiating these lesions. By classifying pigmented lesions based on clinical and histological features, we emphasize the need for a structured approach to diagnosis. The study incorporates a retrospective analysis of cases from our oral medicine experience, utilizing clinical pictures and relevant histology. Our findings aim to enhance early and precise diagnosis, improving patient management and outcomes in dental and medical practice. This paper examines the clinical differentiation of pigmented lesions in the oral mucosa, which poses significant diagnostic challenges across dental and medical disciplines due to their spectrum from benign to potentially malignant conditions. Through a literature review and analysis of clinical cases, this study clarifies current diagnostic methodologies, with an emphasis on differential diagnosis, to provide a practical guide for clinicians. The classification of pigmented lesions, such as endogenous, focal melanocytic, and multifocal pigmentation, based on clinical and histological features, highlights the necessity for a structured and informed approach. A retrospective examination of cases from our oral medicine and pathology clinic, coupled with analysis of photographic and histological records, aids in classifying these lesions. This fosters a better understanding and promotes informed discussions among clinicians, ultimately aiming to enhance early and precise diagnosis, thus improving patient management and outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Primary cutaneous lymphomas (PCLs) are rare forms of skin cancer arising from certain types of white blood cell. They affect the skin without spreading to other parts of the body initially. Understanding them is crucial as they require different treatments compared to other skin cancers. However, diagnosing PCLs is tricky because they can look similar to other skin conditions. We are proposing to use a type of ultrasound called high-frequency ultrasound (HFUS) to better understand how PCLs appear under the skin. By doing this, we hope to improve our ability to identify PCLs accurately and quickly. This could lead to better treatment decisions and outcomes for patients with PCLs. Background: Primary cutaneous lymphoma (PCL) is a rare form of extranodal non-Hodgkin's lymphoma characterized by malignant lymphocytes confined to the skin. Accurate diagnosis and staging are crucial for optimal management, yet radiological literature on imaging PCL remains limited. This study aims to delineate the imaging characteristics of PCLs using high and ultra-high frequency ultrasound (UHFUS) and proposes a classification system based on ultrasound findings. Methods: A cohort of 88 individuals with suspected PCL underwent high-resolution ultrasound (HRUS) and color Doppler examination of lesions. Lesions were categorized based on sonographic appearance, and subsequent histopathological assessment confirmed the diagnosis. Results: Ultrasound imaging revealed distinct patterns for primary cutaneous T-cell lymphomas (PCTCL) and primary cutaneous B-cell lymphomas (PCBCL), with characteristic features such as hypoechoic nodules, pseudonodular lesions, and dermal infiltration. Histopathological analysis confirmed the ultrasound findings, supporting the proposed classification system. Conclusions: Ultrasonography, particularly UHFUS, offers valuable insights into the imaging characteristics of primary cutaneous lymphomas, aiding the accurate diagnosis and assessment of treatment response. The proposed classification system based on ultrasound findings enhances the diagnostic approach to PCLs, and paves the way for improved patient care and management strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma is particularly common and its incidence is increasing. Effective treatment is needed to prevent local recurrence and metastasis. The aim of our systematic review was to assess the potential added value of Mohs micrographic surgery compared with conventional excision. The majority of included studies showed a lower risk of recurrence when Mohs micrographic surgery was used to treat cutaneous squamous cell carcinoma. In addition, Mohs micrographic surgery offers advantages for tumors located in aesthetically or anatomically challenging areas. However, this technique requires a certain level of expertise and additional time and resources. Background: The first-line treatment of the localized form of cutaneous squamous cell carcinoma (cSCC) remains surgical excision. Either conventional excision (CE) with margins or Mohs micrographic surgery (MMS) may be preferred, depending on the risk factors of cSCC, the characteristics of the tumor, and the available technical facilities. Methods: This article presents a systematic review of the current literature spanning from 1974 to 2023, comparing outcomes of cSCC treated with MMS versus cSCC treated with conventional excision. Results: Out of the 6821 records identified through the database search, a total of 156 studies were screened, of which 10 were included in the review. The majority of the included studies showed that treatment of cSCC with MMS consistently exhibits a significantly lower risk of recurrence compared to treatment with CE. In addition, MMS is emerging as the preferred technique for the resection of cSCC located in aesthetically or functionally challenging anatomical areas. Conclusion: The studies generally demonstrate that MMS is a safer and more effective treatment of cSCC than CE. Nevertheless, outcomes such as recurrence rates and cost-effectiveness should be assessed more precisely, in order to allow for a more tailored approach in determining the appropriate indication for the use of MMS. [ABSTRACT FROM AUTHOR]

Simple Summary: Advancements in immune, targeted, and regional therapies have emerged in the past fifteen years in the management of high-risk, advanced, and metastatic melanomas. Rare melanoma variants include acral, mucosal, uveal, and desmoplastic melanoma. Though underrepresented in larger landmark trials for modern therapeutic options, results from these trials have been extrapolated and applied in the management of these rarer subtypes of melanoma. This article aims to review the current treatment recommendations for acral, mucosal, uveal, and desmoplastic melanomas. Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them. [ABSTRACT FROM AUTHOR]

Simple Summary: While the initial favorable efficacy and safety profile for a novel diffusing alpha-emitter radiation therapy (Alpha DaRT) have been previously demonstrated, the longer-term safety and durability of the treatment are unknown. In this pooled analysis of 81 treated head and neck or skin tumors from four clinical trials with a median follow-up of 14 months, a complete response was observed in 89% of treated lesions, two-year local recurrence-free survival was 77%, and there were no grade 2 or higher late toxicities observed. These results suggest that Alpha DaRT is a safe and effective treatment for skin and head and neck tumors. The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2–51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63–87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial. [ABSTRACT FROM AUTHOR]

Raman microspectroscopy has become an effective method for analyzing the molecular appearance of biomarkers in skin tissue. For the first time, we acquired in vitro Raman spectra of healthy and malignant skin tissues, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), at 532 and 785 nm laser excitation wavelengths in the wavenumber ranges of 900–1800 cm−1 and 2800–3100 cm−1 and analyzed them to find spectral features for differentiation between the three classes of the samples. The intensity ratios of the bands at 1268, 1336, and 1445 cm−1 appeared to be the most reliable criteria for the three-class differentiation at 532 nm excitation, whereas the bands from the higher wavenumber region (2850, 2880, and 2930 cm−1) were a robust measure of the increased protein/lipid ratio in the tumors at both excitation wavelengths. Selecting ratios of the three bands from the merged (532 + 785) dataset made it possible to increase the accuracy to 87% for the three classes and reach the specificities for BCC + SCC equal to 87% and 81% for the sensitivities of 95% and 99%, respectively. Development of multi-wavelength excitation Raman spectroscopic techniques provides a versatile non-invasive tool for research of the processes in malignant skin tumors, as well as other forms of cancer. [ABSTRACT FROM AUTHOR]

Nerve sheath myxoma (NSM) is a rare benign peripheral nerve sheath tumor that affects young adults. NSMs are asymptomatic, slow-growing swellings located in the upper extremities, more rarely in the lower extremities. Given the high risk of recurrence, it is recommended to perform a complete exeresis. To our knowledge, the evolution and management of NMS during pregnancy have not been described yet. We report the first case of recurrent pretibial NSM in a pregnant girl and its follow-up and outcome during and after pregnancy. NSM is difficult to diagnose clinically or using imaging. The final diagnosis remains histopathological. It is known how various types of benign and malignant skin tumors can develop or change during pregnancy. With our case, however, we documented that pregnancy does not affect the growth and evolution of NSM. Given the benign nature of the lesions and their tendency to grow slowly, during pregnancy, follow-up of NSMs can be conducted through ultrasonography and surgical treatment postponed after delivery. Our case highlights the importance of careful monitoring and individualized decision making, especially in rare scenarios such as NSM, where data on the progression of benign lesions are limited. Our case highlights the importance of a careful monitoring and a tailored treatment in rare scenarios such as NSM, where data on the progression of benign lesions are limited. Considering the benign nature of the lesions and their tendency to grow slowly, follow-up of NSMs during pregnancy can be conducted through ultrasonography, and surgical treatment can be postponed after delivery. [ABSTRACT FROM AUTHOR]

Warthin tumors (WTs) are the second most common salivary gland tumors, most commonly found in the tail of the parotid gland. The lymphoid components of a WT may also serve as a site for tumor-to-tumor metastasis. This report describes the metastasis of cutaneous squamous cell carcinoma (cSCC) from the preauricular region to a parotid WT. A 68-year-old male patient was admitted to the Department of Cranio-Maxillofacial Surgery of the Jagiellonian University in Cracow, Poland, with a two-year history of a growing, painless skin tumor of the right preauricular region. The patient was eligible for surgical treatment with elective neck dissection at the Va, III, II, I levels with parotidectomy and the excision of the cSCC. In the histopathological examination of the components of the surgical specimen beside the primary cutaneous squamous cell carcinoma (cSCC), a parotid WT was found; in the majority, it was occupied and destroyed by the metastatic cSCC and radically removed. After a tumor board consultation, due to the advanced stage (pT3N2b LVI2 PNI0 R0), with three intraparotid lymph node metastases and LVI2, the patient was authorized for postoperative radiotherapy. In conclusion, tumor-to-tumor metastasis is an extremely rare entity. Surgery is the standard of care for both WTs and head and neck cSCC. In most cases, metastasis into the parotid gland can be successfully treated with superficial parotidectomy with facial nerve preservation. Dissemination into the parotid gland requires elective neck dissection, as well as adjuvant treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The study examined the relationship between Human Papillomavirus (HPV) and various types of skin cancer, including squamous cell carcinoma, basal cell carcinoma, and melanoma. It aimed to assess how HPV influenced the likelihood of developing these cancers, considering factors such as age, gender, urbanization, and existing health conditions. Through statistical models, the research quantified the risk of skin cancer in individuals with HPV compared to those without, underscoring how behaviors related to sun exposure and protection practices could alter these risks. The findings were crucial for guiding prevention and treatment strategies and were of significant interest to medical professionals and public health policymakers. Overall, the study enhanced our understanding of the risks associated with HPV, potentially leading to more effective health interventions. Human papillomavirus (HPV) has been implicated in various cancers, including those affecting the skin. The study assessed the long-term risk of skin cancer associated with HPV infection in Taiwan region, using data from the National Health Insurance Research Database between 2007 and 2015. Our analysis revealed a significant increase in skin cancer risk among those with HPV, particularly for squamous cell carcinoma (SCC), the subtype with the highest observed adjusted hazard ratio (aHR) = 5.97, 95% CI: 4.96–7.19). The overall aHR for HPV-related skin cancer was 5.22 (95% CI: 4.70–5.80), indicating a notably higher risk in the HPV-positive group. The risk of skin cancer was further stratified by type, with basal cell carcinoma (aHR = 4.88, 95% CI: 4.14–5.74), and melanoma (aHR = 4.36, 95% CI: 2.76–6.89) also showing significant associations with HPV. The study also highlighted regional variations, with increased risks in southern Taiwan and the Kaohsiung-Pingtung area. Key findings emphasize the importance of sun protection, particularly in regions of high UV exposure and among individuals in high-risk occupations. This research contributes to a better understanding of the complex interactions between HPV and skin cancer risk, reinforcing the importance of preventive strategies in public health. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the characteristics of metastatic cutaneous squamous cell carcinoma (cSCC) to improve patient risk stratification. By comparing patients with metastatic and non-metastatic cSCC, we analyzed cSCC skin samples for histological parameters and gene expression profiles. Out of 770 genes tested, 67 were differentially expressed in metastatic cSCC. These were mainly related to immune regulation, skin integrity, angiogenesis, cell migration, and proliferation. The findings suggest that combining histological and molecular profiles can help identify features specific to metastatic cSCC, potentially enhancing patient risk assessment. Background: A subset of patients affected by cutaneous squamous cell carcinoma (cSCC) can exhibit locally invasive or metastatic tumors. Different staging classification systems are currently in use for cSCC. However, precise patient risk stratification has yet to be reached in clinical practice. The study aims to identify specific histological and molecular parameters characterizing metastatic cSCC. Methods: Patients affected by metastatic and non-metastatic cSCC (controls) were included in the present study and matched for clinical and histological characteristics. Skin samples from primary tumors were revised for several histological parameters and also underwent gene expression profiling with a commercially available panel testing 770 different genes. Results: In total, 48 subjects were enrolled in the study (24 cases, 24 controls); 67 genes were found to be differentially expressed between metastatic and non-metastatic cSCC. Most such genes were involved in immune regulation, skin integrity, angiogenesis, cell migration and proliferation. Conclusion: The combination of histological and molecular profiles of cSCCs allows the identification of features specific to metastatic cSCC, with potential implications for more precise patient risk stratification. [ABSTRACT FROM AUTHOR]

Simple Summary: This study introduces a groundbreaking method known as the true free-style capillary perforator flap, revolutionizing the approach to reconstructing facial skin defects, such as skin cancer. By meticulously employing a flap design technique that integrates principles such as finger-pinching and alignment with wrinkle directions, the study demonstrates successful reconstructions across various facial regions, including the infraorbital area, nose, and cheek, with a remarkable reduction in postoperative complications. Its contribution lies not only in its clinical success but also in its potential to improve patients' quality of life by offering a reliable and aesthetically pleasing solution to facial skin defects. The true free-style capillary perforator flap stands poised to become a cornerstone in the management of facial skin defects, paving the way for enhanced patient care and outcomes in the realm of reconstructive surgery. This study introduces a free-style perforator based island flap (PBIF) for the reconstruction of skin defects. From March 2012 to December 2022, a retrospective investigation was conducted on patients who underwent reconstruction for facial defects due to skin cancer. Data on the patients' gender, age, anesthesia method, diagnosis, defect location, flap size, complications, and follow-up periods were collected. There are several principles for designing the PBIF: finger-pinching method, alignment with the direction of wrinkles, the smaller width and longer length of the flap, and proximal attachment to the muscle. A total of 32 patients were included, with an average age of 63.6 years. Surgeries were performed in various regions, such as the infraorbital area, nose, cheek, philtrum, and the anterior/posterior/inferior auricular regions, with an average flap size of 7.63 cm2. There were no complications, such as venous congestion or vascular insufficiency in the skin flaps, although one case required revisional closure due to flap disruption. The PBIF is a useful and effective method for the restoration of facial defects. This method can provide simple yet aesthetically satisfying results, showing stable outcomes without complex surgeries or complications. This study indicates the potential for this method to be more widely employed in reconstructive surgeries in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explored advanced diagnostic methods that are used for identifying skin cancer in high-risk melanoma patients. A total of 410 patients were examined using a combination of three advanced imaging techniques: 3D total body photography, digital dermoscopy, and reflectance confocal microscopy. These methods were used in addition to regular skin exams. Results showed that the specialized imaging detected 16 melanomas in 39 removed pigmented lesions, while regular exams detected only 7 melanomas in 163 removed lesions. This indicates that specialized imaging was much more efficient. Each imaging method found melanomas that the others did not. The study concludes that combining these three imaging techniques improves melanoma detection and reduces unnecessary skin removals in high-risk patients. Modern diagnostic procedures, such as three-dimensional total body photography (3D-TBP), digital dermoscopy (DD), and reflectance confocal microscopy (RCM), can improve melanoma diagnosis, particularly in high-risk patients. This study assessed the benefits of combining these advanced imaging techniques in a three-step programme in managing high-risk patients. This study included 410 high-risk melanoma patients who underwent a specialised imaging consultation in addition to their regular skin examinations in outpatient care. At each visit, the patients underwent a 3D-TBP, a DD for suspicious findings, and an RCM for unclear DD findings. The histological findings of excisions initiated based on imaging consultation and outpatient care were compared. Imaging consultation detected sixteen confirmed melanomas (eight invasive and eight in situ) in 39 excised pigmented lesions. Outpatient care examination detected seven confirmed melanomas (one invasive and six in situ) in 163 excised melanocytic lesions. The number needed to excise (NNE) in the imaging consultation was significantly lower than that in the outpatient care (2.4 vs. 23.3). The NNE was 2.6 for DD and 2.3 for RCM. DD, 3D-TBP, or RCM detected melanomas that were not detected by the other imaging methods. The three-step imaging programme improves melanoma detection and reduces the number of unnecessary excisions in high-risk patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Basal Cell Carcinoma is the most prevalent cancer in the white population, with a 30% lifetime risk for individuals with fair skin. The main treatment goal is to completely remove the tumor while preserving function and appearance. Surgery is usually the preferred method due to its high success rates and the ability to verify that the entire tumor has been excised. However, topical and intralesional immunotherapy, although traditionally secondary to surgery, have demonstrated effectiveness and good cosmetic outcomes. These non-surgical treatments are valuable alternatives for patients who cannot undergo surgery. The objectives of this review are to summarize the current state of topical and intralesional immunotherapy treatments for BCC and to evaluate their potential as effective alternatives for certain patient populations. Basal Cell Carcinoma (BCC) is the most common type of cancer among the white population. Individuals with fair skin have an average lifetime risk of around 30% for developing BCC, and there is a noticeable upward trend in its incidence rate. The principal treatment objectives for BCC involve achieving the total excision of the tumor while maximizing the preservation of function and cosmesis. Surgery is considered the treatment of choice for BCC for two main reasons: it allows for the highest cure rates and facilitates histological control of resection margins. However, in the subgroup of patients with low-risk recurrence or medical contraindications for surgery, new non-surgical treatment alternatives can provide an excellent oncological and cosmetic outcome. An evident and justified instance of these local therapies occurred during the COVID-19 pandemic, a period when surgical interventions carried out in hospital settings were not a viable option. [ABSTRACT FROM AUTHOR]

Simple Summary: Routine resection of surgical scars could prevent scar recurrences after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases and pseudomyxoma peritonei. However, there is no clear evidence for resecting all surgical scars, irrespective of macroscopic suspicion of scar metastases, and scar resection is associated with wound complications. Careful macroscopic assessment of surgical scars is needed to avoid routine scar resection. This study aimed to analyze the correlation between macroscopically suspected and microscopically confirmed scar metastases, and to analyze the prognostic impact of not undergoing routine scar resection. This study showed that occult scar metastases were uncommon and patients not undergoing routine scar resection did not have worse recurrence-free or overall survival compared with those undergoing scar resection. Therefore, macroscopically benign-appearing scars can be left without resection, though resection should be performed in case of uncertainty. Background: Careful macroscopic assessment of surgical scars is needed to avoid routine scar resection during cytoreductive surgery (CRS) for peritoneal metastases (PM). This study aimed to analyze the correlation between macroscopically suspected and microscopically confirmed scar metastases (SMs), and to analyze the prognostic impact of not undergoing routine scar resection. Method: All patients with previous surgery, treated with CRS and hyperthermic intraperitoneal chemotherapy, for colorectal PM or pseudomyxoma peritonei (PMP), at Uppsala University Hospital in 2013–2021, were included. Macroscopic SMs in surgical reports were compared with histopathological analyses. Results: In total, 227 patients were included. Among colorectal PM patients (n = 156), SM was macroscopically suspected in 41 (26%) patients, and 63 (40%) underwent scar resection. SM was confirmed in 19 (30%). Among patients with macroscopic suspicion, 45% had confirmed SM (positive predictive value, PPV). A total of 1 of 23 (4%) patients with no macroscopic suspicion had SM (negative predictive value, NPV = 96%). Among the PMP patients (n = 71), SM was macroscopically suspected in 13 (18%), and 28 (39%) underwent scar resection, of whom 12 (43%) had SM. The PPV was 77%. Occult SM was found in 1 of 14 (NPV = 93%). Not undergoing routine scar resection did not affect recurrence-free survival (RFS, p = 0.2) or overall survival (OS, p = 0.1) in colorectal PM patients or PMP patients (RFS p = 0.7, OS p = 0.7). Conclusion: Occult SM is uncommon and scar resection does not affect RFS or OS. Therefore, macroscopically benign-appearing scars can be left without resection, though resection should be performed upon suspicion or uncertainty. [ABSTRACT FROM AUTHOR]

Simple Summary: Anti-cancer treatments often entail a spectrum of adverse effects, and among these, skin cancers have been under significant scrutiny. From traditional immunosuppressants such as methotrexate to chemotherapeutic agents such as fludarabine and hydroxyurea, as well as from new targeted therapies such as ibrutinib and JAK inhibitors to MAP kinase pathway inhibitors and sonic hedgehog pathway inhibitors, each treatment modality poses unique mechanisms of action and associated risks of skin cancer. In addition, the role of radiotherapy in inducing secondary skin cancers underscores the long-term consequences of therapeutic interventions. It is crucial to ascertain whether a specific therapy increases the risk of skin cancer so that appropriate screening measures can be implemented before and during treatment. Our comprehensive review not only investigates various medications and treatment modalities linked with heightened skin cancer risks, elucidating their mechanisms of action and relevant properties, but also proposes effective strategies for managing patients undergoing such therapies. Skin cancers involve a significant concern in cancer therapy due to their association with various treatment modalities. This comprehensive review explores the increased risk of skin cancers linked to different anti-cancer treatments, including classic immunosuppressants such as methotrexate (MTX), chemotherapeutic agents such as fludarabine and hydroxyurea (HU), targeted therapies like ibrutinib and Janus Kinase inhibitors (JAKi), mitogen-activated protein kinase pathway (MAPKP) inhibitors, sonic hedgehog pathway (SHHP) inhibitors, and radiotherapy. MTX, a widely used immunosuppressant in different fields, is associated with basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and cutaneous melanoma (CM), particularly at higher dosages. Fludarabine, HU, and other chemotherapeutic agents increase the risk of non-melanoma skin cancers (NMSCs), including cSCC and BCC. Targeted therapies like ibrutinib and JAKi have been linked to an elevated incidence of NMSCs and CM. MAPKP inhibitors, particularly BRAF inhibitors like vemurafenib, are associated with the development of cSCCs and second primary melanomas (SPMs). SHHP inhibitors like vismodegib have been linked to the emergence of cSCCs following treatment for BCC. Additionally, radiotherapy carries carcinogenic risks, especially for BCCs, with increased risks, especially with younger age at the moment of exposure. Understanding these risks and implementing appropriate screening is crucial for effectively managing patients undergoing anti-cancer therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma (cSCC) ranks among the malignancies with the most pronounced mutation burdens. Understanding its genetic aspects is crucial for improving patient care. This retrospective case-control study compares the molecular profiles of cSCCs in the head and neck regions prone to local recurrence against those without relapse, aiming to identify predictive markers for prognosis and therapy. Using a next-generation sequencing (NGS) array, histological samples from cSCC patients were analyzed, highlighting the most frequently mutated genes in cSCC. Controls displayed a higher mutation count, thus potentially enhancing tumor antigen presentation for the immune system. This immune response might prevent future recurrences, emphasizing the immune system's role in cSCC. The study underscores the importance of novel therapies that leverage the immune system. Cutaneous squamous cell carcinoma is a prevalent malignancy with a rising incidence and a notably high mutational load. Exploring the genetic nuances of cSCC and investigating molecular approaches stands as a potential avenue for improving outcomes in high-risk patients. This retrospective case-control study involved two cohorts, one of 14 patients (the "discovery cohort") and the other of 12 patients (the "validation cohort"), with cSCC located in the head/neck anatomical region and diagnosed at the pT2 stage. Overall, cases developed early local relapses of the disease, whereas controls never relapsed during the entire follow-up period. A next-generation sequencing (NGS) approach conducted on histological samples revealed that TP53 and CDKN2A were the most frequently mutated genes in our series. No specific mutations were identified as potential prognostic or therapeutic targets. Controls exhibited a tendency toward a higher mutational rate compared to cases. It is possible that an increased number of mutations could prompt the cSCC to expose more antigens, becoming more immunogenic and facilitating recognition by the immune system. This could enhance and sustain the immunological response, potentially preventing future recurrences. [ABSTRACT FROM AUTHOR]

Simple Summary: For melanoma patients, the most promising curative treatment is immunotherapy. Here, we summarise current immunotherapy strategies and their indications and challenges, and provide future directions of immunotherapy development. Several therapy resistance mechanisms have been described, resulting in primary refractory disease or resistance development in patients. Our increasing knowledge of immune regulation within the tumour microenvironment identifies potential alternate immunotherapy targets, including CD155. CD155 and its receptor, TIGIT, have been shown to be highly expressed in therapy-resistant melanoma cells and interference with both is therefore considered a possible immunotherapeutic strategy. This review describes the immune regulation within the melanoma tumour microenvironment, how and why immunotherapies work, and why CD155 might be an ideal target for the next generation of anti-melanoma immunotherapies. Melanoma is commonly diagnosed in a younger population than most other solid malignancies and, in Australia and most of the world, is the leading cause of skin-cancer-related death. Melanoma is a cancer type with high immunogenicity; thus, immunotherapies are used as first-line treatment for advanced melanoma patients. Although immunotherapies are working well, not all the patients are benefitting from them. A lack of a comprehensive understanding of immune regulation in the melanoma tumour microenvironment is a major challenge of patient stratification. Overexpression of CD155 has been reported as a key factor in melanoma immune regulation for the development of therapy resistance. A more thorough understanding of the actions of current immunotherapy strategies, their effects on immune cell subsets, and the roles that CD155 plays are essential for a rational design of novel targets of anti-cancer immunotherapies. In this review, we comprehensively discuss current anti-melanoma immunotherapy strategies and the immune response contribution of different cell lineages, including tumour endothelial cells, myeloid-derived suppressor cells, cytotoxic T cells, cancer-associated fibroblast, and nature killer cells. Finally, we explore the impact of CD155 and its receptors DNAM-1, TIGIT, and CD96 on immune cells, especially in the context of the melanoma tumour microenvironment and anti-cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Although not completely understood, the role of the Hedgehog-GLI (HH-GLI) signaling pathway in melanoma and epithelial skin tumors has been reported before. In this study, we confirmed in various melanoma cell line models that keratin 16 (KRT16) and S100 Calcium-Binding Protein A7 (S100A7) are transcriptional targets of GLI Family Zinc Finger (GLI) proteins. Besides their important role in protecting and maintaining the epidermal barrier, keratins are somehow tightly connected with the S100 family of proteins. We found that stronger expression of KRT16 indeed corresponds to stronger expression of S100A7 in our clinical melanoma samples. We also report a trend regarding staining of GLI1, which corresponds to stronger staining of GLI3, KRT16, and S100A7 proteins. The most interesting of our findings is that all the proteins are detected specifically in the epidermis overlying the tumor, but rarely in the tumor itself. The examined proteins were also not detected in the healthy epidermis at the edges of the sample, suggesting that the staining is specific to the epidermis overlaying the tumor mass. Of all proteins, only S100A7 demonstrated a statistically significant trend regarding tumor staging and staining intensity. Results from our clinical samples prove that immune infiltration is an important feature of melanoma. Pigmentophages and tumor-infiltrating lymphocytes (TIL) demonstrate a significant association with tumor stage, while mononuclear cells are equally present in all stages. For S100A7, we found an association between the number of TILs and staining intensity. Considering these new findings presented in our study, we suggest a more detailed examination of the possible role of the S100A7 protein as a biomarker in melanoma. [ABSTRACT FROM AUTHOR]