Search Results (385)

Background/Objectives: Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with a 40% recurrence rate. However, reliable biomarkers for early recurrence detection or treatment guidance are lacking, especially for virus-negative tumors. Circulating tumor DNA (ctDNA), a fragment of tumor-derived cell-free DNA in blood, has emerged across multiple cancers as a minimally invasive precision biomarker to detect minimal residual disease (MRD); predict recurrence; and monitor treatment response. This review’s objective was to summarize recent advances in ctDNA as a tool for therapeutic decision-making in MCC, contextualized by findings in other malignancies. Methods: A comprehensive literature review was performed, focusing on studies published between 2016 and 2026 that evaluate ctDNA in MCC and other cancers. Key prospective trials, observational studies, and case reports were identified through PubMed and relevant conference proceedings. Data on ctDNA assay methods (tumor-informed vs. tumor-agnostic), clinical sensitivity, lead time for recurrence detection, and predictive value for therapy response were extracted and synthesized. Results: Across cancers such as colorectal, lung, and melanoma, ctDNA positivity after curative treatment predicts relapse months in advance of imaging and can guide adjuvant therapy decisions. In MCC, recent studies demonstrate that ctDNA levels correlate with MCC tumor burden and exhibit high sensitivity and specificity for clinically evident disease. Stage I-III MCC patients who were ctDNA-positive within four months of treatment had a 7.4-fold higher recurrence risk within the subsequent 12–18 months of follow-up. Serial ctDNA monitoring may enable earlier intervention in otherwise asymptomatic ctDNA-positive MCC cases, helping distinguish responders from non-responders. Conclusions: ctDNA is an emerging precision biomarker that offers significant prognostic and surveillance utility in MCC. It enables earlier detection of recurrence, potentially allowing treatment to begin before clinical disease manifests. It also helps stratify patients by risk and treatment response, informing personalized surveillance intensity and therapeutic choices. Integrating ctDNA monitoring into MCC management could improve outcomes by guiding timely interventions, although prospective trials are needed to confirm that ctDNA-guided decisions translate to improved patient survival. Formal cost-effectiveness analyses have not yet been conducted and represent an important area for future investigation. Full article

Melanoma incidence rates have also been steadily increasing, emphasizing the need for improved prognostic and diagnostic tools with the goal of enhancing patients’ outcomes. Biomarkers in melanoma have emerged as an important component of melanoma management, offering insight into disease progression, tumor biology, and the potential for judging treatment responses. Traditionally, blood and immunohistochemical markers such as lactate dehydrogenase (LDH), S100 calcium-binding protein (S100B), human melanoma black-45 (HMB-45), and SRY-box transcription factor 10 (SOX10) have been widely used in melanoma diagnosis, staging, and monitoring. However, their clinical use has been limited because of their low specificity, especially in patients with early-stage disease. This has led to the development of molecular and genetic biomarkers, including BRAF, NRAS, and KIT mutations, which improved patients’ risk stratification and enabled targeted therapies, and gene expression signature assays such as DecisionDx (Castle Biosciences) and SkylineDx (Merlin) that are already used in clinics to help with surgical decisions and to assess patients’ prognosis. Other circulating biomarkers, including microRNAs, circulating tumor DNA and circulating tumor cells, have been developed to provide minimally invasive approaches to monitor tumor evolution and detect recurrence. However, none of these new approaches are used in clinics due to their low specificity and/or sensitivity. Additionally, nomograms or predictive models have been created using biomarkers and clinicopathologic data to assess patients’ outcomes and survival. While significant progress has been made, the integration of melanoma biomarkers into routine clinical practice remains limited. This review summarizes current advancements in melanoma biomarkers, including traditional serum and immunohistochemical markers, as well as developments in molecular, genetic, circulating, and predictive biomarker approaches. Full article

Cutaneous squamous cell carcinoma (cSCC) is one of the most common non-melanoma skin cancers worldwide. Although surgery and adjuvant therapies are often effective, the treatment of high-risk or advanced lesions remains challenging due to recurrence, resistance, toxicity, and limited long-term control. Natural compounds have, therefore, gained interest as multi-target agents for cancer prevention and treatment. This systematic review aimed to evaluate the antitumoral activity of natural compounds against cSCC. A systematic literature search was conducted following PRISMA 2020 guidelines. Sixty studies met the inclusion criteria and were analyzed using a conservative, mechanism-based classification framework. The included studies evaluated purified compounds, crude extracts, essential oils, formulations, photodynamic agents, and combination treatments. Despite chemical diversity, antitumoral activity converged on defined biological processes, including apoptosis, non-apoptotic regulated cell death, redox modulation, oncogenic signaling inhibition, cell-cycle arrest, epigenetic regulation, photodynamic ROS generation, and chemopreventive or immune-mediated mechanisms. Mechanistic specificity was higher among purified compounds, while complex extracts showed broader, context-dependent effects. Several agents demonstrated consistent in vitro and in vivo activity, which supports their translational relevance. Natural compounds target shared biological vulnerabilities in cSCC through mechanistically convergent pathways. The framework presented here supports mechanism-guided prioritization and may facilitate the translation of promising compounds into clinically relevant strategies. Full article

A critical gap in current efficiency in melanoma patient treatment is the lack of a fully integrated, functional understanding of tumor evolution over time. Recent advances have fundamentally reshaped our understanding of melanoma biology, while increasing clinical complexity has highlighted the need for more comprehensive and biologically informed clinical decision-support frameworks. We propose the implementation of a multimodal disease profiling framework as a core clinical decision-support asset, enhancing treatment optimization across the full disease course in melanoma patients. By integrating proteogenomics, AI-driven digital image analysis, and structured longitudinal clinical metadata, multimodal disease profiling could provide a comprehensive and dynamically evolving view of each patient’s disease. Proteogenomics reveals tumor signaling activity, protein complex dynamics, and emerging therapeutic vulnerabilities that may drive progression and resistance. In parallel, AI-enabled digital pathology analysis characterizes tumor morphology, clonal heterogeneity, and immune context, capturing spatial and functional changes associated with metastatic transition. When combined with longitudinal clinical data, these layers enable patient-specific models tracking tumor evolution, metastasis, and treatment exposure. Leveraging one of the largest melanoma biobank and database resources at the European Cancer Moonshot Center in Lund, our strategy directly addresses the recurrent transition from primary tumors to metastatic disease. This strategy positions multimodal disease profiling as a critical enabler of precision melanoma care by providing biologically grounded, evidence-based decision support, facilitating rapid and structured case assessment through multimodal insights, enabling prediction of treatment response, resistance, and disease trajectory, and supporting adaptive, evidence-informed therapeutic decision-making. Full article

Mohs Micrographic Surgery (MMS) is considered the most conservative and preserving procedure for removing cutaneous tumors. The major disadvantage of MMS is that tumor involvement in tissue may be underestimated. This may lead to large excisions necessitating complex reconstruction with profound effects on cosmetic results. Some patients refuse complex reconstruction and demand simple closure of post-MMS skin defects. This retrospective cohort study describes our technique of serial Mohs excisions of large non-melanoma skin cancers for patients refusing flaps or skin graft reconstructions. A total of 51 patients who underwent MMS according to the described technique February 2020–May 2021 were included. The mean age was 76.5 (range 63–94) years and 55% were male. More than half of the lesions were on the nose. Mean lesion sizes were 14.25–55 mm depending on location. Most cases required two surgeries and only one needed a third surgery. Postsurgical defects were repaired using primary closure in 90% of cases. Mean follow-up was 31 months (range 6–48) with no evidence of local recurrence. In conclusion, this approach of serial excisions with MMS can be performed safely and achieve better cosmetic outcomes for patients presenting with large skin tumors of the face or other functionally important areas. Full article

Background: Elderly patients have low utilization of adjuvant ICIs, although they achieve similar RFS benefits as younger patients. It remains unclear why elderly patients use adjuvant ICIs less frequently and whether toxicity impacts treatment utilization. Methods: Adult patients with stage III melanoma treated from 2017 to 2023 at a single academic cancer center were retrospectively identified. Multivariable logistic regressions evaluated the association of age with receipt of adjuvant ICIs and toxicity. RFS was assessed using Kaplan–Meier and multivariable Cox proportional hazards regression. Results: Among 240 patients, those aged ≥ 75 years were less likely to receive adjuvant ICI than those aged 18–74 years (aOR: 0.30; 95% CI: 0.11–0.80). Among 53 (22.1%) patients who did not receive adjuvant ICI, 58% declined treatment, 15% were not offered adjuvant ICI by provider, 9% had a comorbid autoimmunity, and 6% had another comorbidity. A total of 12% of patients aged 75–80 years old declined treatment versus 33% of those aged 80–90 years old. Older age was not associated with toxicity, treatment interruption, or discontinuation from adjuvant ICI. Adjuvant ICI was associated with low recurrence (aHR: 0.76; 95% CI: 0.63–0.92), whereas age ≥ 75 years was associated with higher recurrence risk (aHR: 1.79; 95% CI: 1.04–3.10) and low overall survival (aHR: 3.07; 95% CI: 1.43–6.57) compared to patients aged 18–74 years. Conclusions: Older patients with stage III melanoma were less likely to receive adjuvant ICIs, despite similar toxicity, treatment interruption, and discontinuation rates across age groups. Because adjuvant therapy is associated with lower recurrence risk, efforts to better understand and address age-related differences in treatment use are warranted. Full article

Background: Immune checkpoint inhibitors (ICIs) can induce a sicca-like syndrome that differs from primary Sjögren’s disease in both immunopathogenesis and clinical phenotype. Despite growing recognition of this entity, data describing real-world management and outcomes, particularly in the context of ICI discontinuation and rechallenge, remain limited. Methods: Patients with new onset of sicca syndrome or exacerbation of previous symptoms following ICI therapy were retrospectively identified and assessed. Results: Fifty-nine patients with diverse malignancies (including melanoma, gastrointestinal, genitourinary, etc.) and sicca syndrome following treatment with ICIs (most often pembrolizumab or nivolumab +/− ipilimumab) were evaluated. Acute-onset dry mouth, primarily CTCAE v6.0 grades 1 (n = 24, 40.7%) and 2 (n = 34, 57.6%), occurred at a median of 104 days after ICI initiation, sometimes with associated dry eye (n = 8, 13.6%). Most were managed conservatively with behavioral modification and over-the-counter therapies alone (n = 37, 62.7%) while others received sialagogues (n = 9, 15.3%), dexamethasone oral rinse (n = 11, 18.6%), and/or systemic corticosteroids (n = 16, 27.1%). Additional management strategies included de-escalation to ICI monotherapy (n = 5, 8.5%) or discontinued ICI (n = 6, 10.2%). Half of patients treated with corticosteroids demonstrated subjective improvement in symptoms while 75% improved following ICI discontinuation. Four patients underwent rechallenge after a median interruption of 564 days; all (n = 4) demonstrated sicca recurrence. Conclusions: In this largest cohort to date of ICI-associated sicca syndrome, we confirm frequent improvement with steroids and/or supportive care and suggest a greater than previously appreciated risk of recurrence with rechallenge. Full article

The role of adjuvant therapy in stage III melanoma is well established in clinical practice. Because stage IIB–IIC melanoma carries a risk of recurrence and melanoma-specific mortality comparable to that of stage III disease, adjuvant approaches have also been developed for patients with thick stage II tumors. Both pembrolizumab and nivolumab have demonstrated efficacy in reducing the risk of local and distant recurrence in patients with high-risk stage II melanoma, whereas evidence supporting the use of BRAF-MEK inhibitors in this setting remains inconclusive. Combinations of immune checkpoint inhibitors, as well as immunotherapy combined with mRNA-based vaccines, are currently under investigation in clinical trials. However, given the non-trivial risk of immune-related adverse events, careful selection of patients with stage II disease who are most likely to derive meaningful benefit from adjuvant therapy is essential. In this context, several clinicopathologic variables and gene expression profiling-based prognostic tools have been proposed to refine risk stratification. To date, however, none of these instruments have been incorporated into routine clinical practice, and no validated predictive biomarkers are available. Accordingly, optimal patient selection for adjuvant therapy remains an important unmet clinical need in early-stage melanoma. Full article

Background: Non-melanoma skin cancers (NMSCs) of the head and neck represent a therapeutic challenge due to the region’s complex anatomy, functional considerations, and frequent involvement of high-risk anatomical zones. Local recurrence remains a clinically significant concern, however real-world data regarding recurrence patterns and associated risk factors in facial NMSCs are limited. Objectives: To evaluate the incidence of local recurrence of facial skin cancers after surgical treatment and to determine clinicopathological and anatomical actors associated with an increased risk of recurrence. Methods: In this single-center retrospective cohort study, consecutive patients undergoing surgical excision of facial NMSC were included. The treatment of choice was always surgical excision under general or local anesthesia, with an adequate margin of macroscopically unchanged tissue. Mohs surgery was not used, and none of the patients received immunosuppression. Clinical and pathological data were extracted from medical records. Histopathological examination constituted the basis for establishing the final clinical diagnosis and thus was not verified otherwise. The primary outcome was histologically confirmed local recurrence defined as the reappearance of a tumor of the same histopathological type at the same anatomical site as the previously excised lesion. Patients in the non-recurrence group were defined as those who did not experience any recurrence within a 5-year follow-up period after the initial surgical treatment. Fisher’s exact test and the Mann–Whitney U test were used for statistical analysis. Logistic regression was performed to explore factors associated with recurrence. Due to incomplete follow-up data for the non-recurrent group, we limited the timing analysis to recurrent cases only, as these limitations precluded the use of standard survival analysis. Results: A total of 302 lesions were analyzed, with recurrence status available for 291 tumors. The overall recurrence rate was 28.52%. Basal cell carcinoma (BCC) was the most common histopathological subtype. Recurrences occurred more frequently in anatomically high-risk areas, particularly the scalp, temple and nose. Infiltrative BCC subtypes demonstrated higher recurrence rates than nodular and superficial subtypes. Patients with recurrent tumors were younger than those without recurrence. A history of prior skin radiotherapy was associated with increased odds of recurrence. Tumor size and surgical margin width were not significantly associated with recurrence. Multivariate models showed limited discriminatory ability, suggesting that additional unmeasured factors contribute to recurrence risk. Conclusions: Local recurrence of non-melanoma skin cancers in the head and neck region remains a substantial clinical concern, particularly in high-risk anatomical sites and tumors with aggressive histopathological features. These findings highlight the importance of long-term follow-up and support further prospective studies to improve recurrence risk assessment and treatment strategies. Full article

Background and Objectives: This study aimed to identify the risk factors of primary cutaneous melanomas associated with microsatellites, satellites, and in-transit metastases. Materials and Methods: We performed a retrospective study on patients diagnosed with invasive primary cutaneous melanomas in two pathology departments. The cases were distributed into two groups, comparing the clinical–pathological features of cases that presented microsatellites, satellites, and in-transit metastases with cases that did not present microsatellites, satellites, and in-transit metastases. Results: From the total number of primary invasive cutaneous melanomas diagnosed (n = 204), 22% presented microsatellites, satellites, and in-transit metastases (n = 46). The presence of microsatellites, satellites, and in-transit metastases was strongly correlated with a Breslow index > 4 mm, a Clark level of IV or V, and a pT3 or pT4 pathological stage (p < 0.0001). Those cases were also associated with lymphovascular invasion (p = 0.0013), ulceration of the primary melanoma (p = 0.0037), and an increased mitotic rate (p = 0.0078). The presence of microsatellites, satellites, and in-transit metastases is associated with higher rates of lymph node metastases (p = 0.0006) and recurrence (p = 0.0282). Conclusions: The most important risk factors associated with microsatellites, satellites, and in-transit metastases are represented by a Breslow index > 4 mm, a Clark level of IV or V, and an advanced pathological stage. Full article

Cutaneous melanoma is an aggressive skin cancer. While laser therapy is established for non-melanoma skin cancers, its role in melanoma remains controversial and largely unsupported by robust clinical evidence. The gold standard for melanoma management remains surgical excision, as it allows for definitive histopathological diagnosis, Breslow thickness measurement, and surgical margin assessment, which are essential for accurate staging. This narrative review analyzed preclinical and clinical studies evaluating various laser modalities, including Nd:YAG, CO₂, pulsed dye, photodynamic therapy (PDT) and photothermal therapy (PTT), for efficacy, recurrence rates, and limitations in cutaneous melanoma management. Nd:YAG laser (1064 nm) showed potential for local control in thin stage I melanomas, reporting a low local recurrence rate of 0–0.7% and favorable 5-year survival in small, non-randomized cohorts. CO₂ laser (10,600 nm) provides effective palliation and local control for in-transit or unresectable metastases, but local recurrence is highly variable, reaching up to 46.7%. Photodynamic therapy showed variable efficacy, although Chlorin e6 achieved complete local regression in a small series of metastases. A critical limitation of laser therapy is the irreversible destruction of tissue, which precludes these vital assessments. Therefore, laser treatment should be cautiously reserved for cases where standard surgery is not feasible, acknowledging that it may interfere with the evaluation of curative outcomes and accurate staging. Laser therapy is a valuable minimally invasive adjunct for local control in selected patients who are poor surgical candidates or require palliative care. Routine use is restricted by the lack of randomized controlled trials. Future studies should prioritize combination strategies with systemic or immunotherapeutic approaches to enhance overall outcomes. Full article

Melanoma adjuvant therapy has substantially improved recurrence-free and distant metastasis-free survival in patients with resected high-risk disease, and more recently, these advances have extended to earlier stages. However, important unmet needs remain, including the management of stage IIIA disease, the optimal treatment strategy after relapse on adjuvant therapy, and the identification of biomarkers capable of refining patient selection. This review summarizes recent advances and unresolved questions in the adjuvant and neoadjuvant treatment of melanoma. We discuss novel systemic strategies, including immune checkpoint inhibitor combinations and personalized neoantigen mRNA vaccines, together with the expanding role of neoadjuvant approaches. We also examine prognostic and predictive tools—such as clinicopathologic models, circulating tumor DNA, serum biomarkers, tumor microenvironment features, and gene expression profiling—that may help better define recurrence risk and therapeutic benefit. Current evidence suggests that although modern therapies have changed the natural history of resected melanoma, a substantial proportion of patients are still overtreated or undertreated when treatment decisions are based on stage alone. Future progress will depend on integrating biological risk stratification with clinical staging and optimizing treatment sequencing across adjuvant and neoadjuvant settings. Full article

Background and Objectives: Tumor-infiltrating lymphocytes (TIL) and the neutrophil-to-lymphocyte ratio (NLR) are each associated with prognosis in melanoma, yet their combined prognostic value remains insufficiently defined. We aimed to assess whether integrating NLR and TILs into a combined immune phenotype improves prediction of recurrence-free survival (RFS) in patients with resected cutaneous melanoma. Materials and Methods: A total of 203 patients were included. Receiver operating characteristic analysis identified an NLR cut-off of 2.75 for RFS, defining low (<2.75) and high (≥2.75) groups. TIL status was dichotomized as present or absent. According to the combined NLR–TIL profile, patients were initially categorized into three immune phenotypes: favorable (low NLR and TIL-positive), intermediate (low NLR and TIL-negative or high NLR and TIL-positive), and unfavorable (high NLR and TIL-negative). For the dichotomized analysis, the intermediate and unfavorable phenotypes were combined and compared with the favorable phenotype. Associations of clinicopathological factors with RFS were evaluated using Kaplan–Meier curves and Cox regression models. Results: The median follow-up was 56 months. In the univariate analysis, stage III disease, greater Breslow thickness, increased mitotic rate, and absence of adjuvant therapy were associated with worse RFS. In addition, patients with an unfavorable immune phenotype had a markedly increased risk of recurrence compared with those in the favorable group (HR 2.86, 95% CI 1.43–5.71; p = 0.004). In multivariate Cox regression analysis, both the unfavorable immune phenotype and stage III disease independently predicted RFS (HR 2.25, 95% CI 1.11–4.54; p = 0.024 and HR 2.13, 95% CI 1.03–4.43; p = 0.041, respectively). Conclusions: Combined assessment of systemic inflammation and tumor-local immune response using NLR and TILs may provide meaningful prognostic stratification in resected cutaneous melanoma. Full article

Circulating tumor DNA (ctDNA) has many potential applications in the management of cancer, including detection, monitoring, and treatment response assessment. This study evaluates pre-treatment ctDNA detection in a single-institution pan-cancer cohort using a highly sensitive tumor-informed ctDNA assay. Participant samples were collected at the University Health Network across six study cohorts. A total of 273 patients with stage II-IV cancers spanning 16 tumor types were analyzed using a personalized tumor-informed assay (RaDaR^®). Harmonized methods were employed to mitigate the impact of variables known to influence ctDNA detection and its quantification. Pre-treatment ctDNA was detected in 83% of participants (226/273) across all stages and cancer types. Detection rates varied by clinical characteristics, including cancer type and stage; ctDNA was detected in 100% of stage IV metastatic recurrent high-grade serous ovarian cancer (HGSOC) patients (n = 8/8) and 54% of stage IV melanoma patients (n = 6/11). The median estimated variant allele fraction (eVAF) across all patients with a positive ctDNA result was 0.25% (range: 0.000029–37.7%), varied by tumor type and increased with cancer stage. A total of 11% of positive samples (24/226) had an eVAF of <0.01%. This pan-cancer ctDNA analysis using a highly sensitive assay reveals high detection rates overall, including ~10% at low levels (<0.01% eVAF), offering a reference for future clinical ctDNA applications and furthering our understanding of factors influencing ctDNA measurements. Full article

Background: Conjunctival melanoma is a rare but potentially aggressive ocular surface malignancy characterized by frequent local recurrence and risk of metastatic spread. In carefully selected cases, depending on tumor extent, clinical course, and patient condition, management may require balancing oncologic control with preservation of the globe, visual function, and quality of life. Case Presentation: We report the case of a 78-year-old woman with amelanotic conjunctival melanoma of the left eye. Initial treatment consisted of wide local excision using a no-touch technique, conjunctival autograft reconstruction, and adjuvant topical Mitomycin C (MMC). During a 10-year follow-up period, the patient developed multiple local recurrences requiring repeated surgical excisions and additional MMC therapy. Despite the chronic relapsing course, useful visual function and globe preservation were maintained. In December 2024, a subcutaneous lesion of the upper eyelid was detected and histopathologically confirmed as locoregional metastasis from the primary conjunctival melanoma. Given the patient’s advanced age, preserved visual function, absence of documented distant metastatic disease, and overall clinical context, management continued with a conservative, eye-preserving approach. Conclusions: This case illustrates that prolonged eye preservation may be achievable in carefully selected patients with recurrent conjunctival melanoma through repeated conservative management. However, this strategy does not eliminate the risk of delayed progression and requires individualized decision-making together with long-term surveillance. Full article