Search Results (223)

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

Background and Clinical Significance: Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a CD30-positive T-cell lymphoproliferative disorder that can clinically resemble various non-melanoma skin cancers, making diagnosis challenging. Although histopathology remains the diagnostic gold standard, non-invasive imaging modalities such as dermoscopy and reflectance confocal microscopy (RCM) are increasingly used as complementary tools to support the differential diagnosis. To date, no data on RCM features of C-ALCL have been described. Case Presentation: We report the case of an 80-year-old man presenting with a rapidly enlarging nodule on the lateral aspect of his right eyelid, providing a detailed account of dermoscopic and RCM findings integrated with clinicopathological correlation. Dermoscopy revealed a red-orange homogeneous background with white streaks, and polymorphic vascular structures, while subsequent RCM (Vivascope 3000 probe) demonstrated marked architectural disarray of the epidermis and dermoepidemal junction, with prominent epidermal involvement characterized by aggregates of highly reflective cells. In the absence of alternative diagnostic patterns, these features raised suspicion for a cutaneous lymphoproliferative disorder, which was later confirmed by histopathological and immunohistochemical analyses. Conclusions: Our findings support the value of RCM as a practical tool in guiding differential diagnosis and biopsy, particularly for rapidly growing lesions located in anatomically sensitive areas. Full article

Background/Objectives: Teledermoscopy may improve melanoma triage by accelerating specialist review and compressing the time to definitive treatment, but its clinical relevance depends on whether faster access is accompanied by detection at a less advanced stage. This study compared teledermoscopy-assisted and conventional referral pathways for cutaneous melanoma as a pathway-level service evaluation. Methods: In this single-center observational cohort, 87 patients with histologically confirmed primary cutaneous melanoma were analyzed, including 43 managed through teledermoscopy-assisted referral and 44 through a conventional pathway. Primary outcomes were time from referral to dermatology consultation, biopsy, and definitive excision. Secondary outcomes included Breslow thickness, mitotic rate, ulceration, stage distribution, early-stage disease, and selected pathway-quality indicators. Results: Teledermoscopy-assisted referral was associated with shorter median times to consultation (9.0 vs. 18.7 days), biopsy (16.6 vs. 30.3 days), and excision (26.9 vs. 43.2 days), all p < 0.001. Patients in the teledermoscopy group had lower Breslow thickness (0.7 vs. 1.5 mm, p < 0.001), lower mitotic rate (1.2 vs. 2.9 mitoses/mm², p < 0.001), a higher proportion of stage 0/I melanoma (79.1% vs. 40.9%; risk ratio 1.93, 95% CI 1.31–2.85), and fewer lesions with Breslow > 2.0 mm (9.3% vs. 36.4%; risk ratio 0.26, 95% CI 0.09–0.70). Conclusions: In this non-randomized cohort, teledermoscopy-assisted referral was associated with faster melanoma care and a more favorable stage profile at excision. Because pathway assignment was not randomized and lesion-level referral urgency was incompletely measured, these findings should be interpreted as associations that support further prospective evaluation rather than as proof of causal stage migration. Full article

Chimeric antigen receptor (CAR) T-cell therapy represents a major advance in modern immunotherapy. This narrative review summarizes evidence from the past five years, including case reports, case series, and clinical trials, on its application beyond hematologic malignancies, focusing on autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), as well as solid tumors including melanoma and primary cutaneous lymphomas. CD19-directed CAR T-cells have demonstrated clinical benefits in SLE and SSc, with sustained immune reset, reduced autoreactive antibody levels, and clinical improvement. In melanoma, CAR T-cells targeting GD2, cMET, and CD20 have shown in vivo expansion and tumor infiltration; however, clinical efficacy remains limited, with transient stabilization or disease progression in most patients. In primary cutaneous lymphomas, early-phase studies with anti-CD70 and anti-CCR4.30 CAR T-cells indicate partial tumor regression and disease stabilization, often requiring additional therapy. Key challenges include limited durability of immune reset due to persistent plasma cells in autoimmune disorders, tumor heterogeneity, antigen loss or overlap, infiltration barriers, resistance mechanisms, and T-cell depletion in solid tumors, collectively reducing response durability and safety. The main toxicities include grade 1–2 cytokine release syndrome and rare hematologic complications, while immune effector cell-associated neurotoxicity syndrome is uncommon. Clinical translation remains limited and requires larger studies to improve efficacy and define safety profiles. Full article

Background and Objectives: Sentinel lymph node biopsy (SLNB) is increasingly used for high-risk, clinically node-negative cutaneous squamous cell carcinoma (cSCC), yet pathological reporting remains binary, lacking morphological stratification. The prognostic relevance of nodal tumor burden subtypes—isolated tumor cells (ITC), micrometastases, and macrometastases—is well established in melanoma and breast cancer but remains uncharacterized in cSCC. We aimed to describe the morphological spectrum of sentinel lymph node involvement in a consecutive institutional cohort and determine whether primary tumor characteristics predict the extent of nodal colonization. Materials and Methods: We conducted a retrospective-observational study at Clinical Center Niš (Serbia) including 35 consecutive clinically N0 high-risk cSCC patients who underwent SLNB using a dual-tracer protocol (⁹⁹mTc-labeled albumin and methylene blue). Sentinel nodes were processed by serial sectioning with hematoxylin-eosin and pancytokeratin (AE1/AE3) immunohistochemistry. Deposits were classified as ITC (≤0.2 mm), micrometastases (>0.2–2.0 mm), or macrometastases (>2.0 mm). Clinicopathologic predictors were evaluated using the Mann–Whitney U test, Fisher’s exact test, the Kruskal–Wallis test, and the Spearman rank correlation test. Results: SLN involvement was identified in 12 of 35 patients (34.3%). Among positive cases, ITC accounted for 6 patients (50.0%), micrometastases for 5 (41.7%), and macrometastasis for 1 (8.3%)—minimal nodal disease constituting 91.7% of positive findings. No primary tumor feature—including diameter, thickness, grade, perineural invasion, or lesion multiplicity—significantly distinguished ITC from overt metastatic deposits. Patients with ITC showed numerically higher median tumor thickness (8.0 mm) than those with micrometastases (4.0 mm), though this did not reach significance (Kruskal–Wallis p = 0.065). Conclusions: SLN positivity in high-risk cSCC is morphologically heterogeneous, with minimal nodal disease predominating. Primary tumor features do not reliably stratify the extent of nodal colonization. Structured tumor-burden reporting—distinguishing ITC, micrometastases, and macrometastases—should be adopted as standard practice to enable meaningful prognostic comparisons and inform individualized management. Full article

Cutaneous melanoma is the most lethal form of skin cancer because of its aggressiveness, rapid metastasis, and high therapeutic resistance. The 2018 World Health Organization (WHO) classification emphasized that melanoma comprises distinct subtypes defined by cumulative sun damage, site of origin, and molecular characteristics, which explain differences in mutational burden, immunogenicity, and treatment response. Immunotherapy with anti-PD-1 therapy such as nivolumab and pembrolizumab changed the therapeutic landscape by restoring CD8+ T-cell activity and improving survival. Still, many patients show primary or acquired resistance influenced by low PD-L1 expression, loss of antigen presentation, tumor metabolic plasticity, and an immunosuppressive microenvironment. Mitochondria are central to this process. They regulate ATP generation through oxidative phosphorylation (OXPHOS), redox control, apoptosis, and the metabolic programming needed for T-cell activation. In the tumor microenvironment (TME), hypoxia, nutrient restriction, and PD-1 signaling reduce mitochondrial biogenesis, increase fission and reactive oxygen species (ROS) accumulation, and lead to exhaustion and impaired effector function. Moreover, tumor cells outcompete immune cells for key nutrients such as glucose and glutamine, while increased lactate production and extracellular acidosis further suppress mitochondrial respiration in T cells. Strategies to overcome resistance include restoring oxidative metabolism, activating PGC-1α, supplying metabolic substrates, and combining checkpoint blockade with inhibitors of glycolysis or glutaminolysis to enhance the immune response. Full article

Background and Objectives: Melanoma is one of the most aggressive malignancies in humans and is associated with an unfavorable prognosis due to its high metastatic potential. In recent decades, increasing incidence and mortality rates have been reported worldwide among Caucasian populations. This study aimed to analyze melanoma incidence and mortality trends in the Republic of Serbia from 2008 to 2022, with a special regard to sex- and age-specific differences. Materials and Methods: A descriptive epidemiological study was conducted using data on all cases of primary cutaneous melanoma (ICD-10 code C43) reported to the Serbian Cancer Registry between 2008 and 2022. Data on newly diagnosed cases and melanoma-related deaths were analyzed by sex and 5-year age groups. Crude rates were calculated per 100,000 populations, whereas age-standardized rates were obtained using direct standardization. Temporal trends were evaluated using the Joinpoint regression analysis. Results: During the study period, 9600 new melanoma cases and 3882 melanoma-related deaths were reported in Serbia. Both incidence and mortality were higher in men (52.5% and 60.1%, respectively). Age-standardized incidence rates remained relatively stable in both sexes, with a slight increase in men (AAPC = 0.9%; 95% CI: −0.5 to 2.3) and a stable trend in women (AAPC = −0.1%; 95% CI: −1.5 to 1.3). Age-standardized mortality rates showed a mild, statistically insignificant decline overall (AAPC = −0.6% in men and −0.9% in women). The calculated mortality-to-incidence ratio (MIR) shows consistently higher values in men compared to women. A significant increase in incidence was observed among men aged 70–74 years (AAPC = 3.1%; p = 0.011), while mortality significantly decreased in women aged 40–44 years (APC = −7.0%; p = 0.017). Conclusions: Melanoma incidence in Serbia remained relatively stable between 2008 and 2022, with a modest increase primarily among older men. Mortality trends showed a slight decline, suggesting potential improvements in early detection and treatment outcomes. Full article

Background/Objectives: During the pandemic, access to healthcare was severely disrupted, inevitably affecting melanoma diagnosis. While this was clearly evident during the pandemic itself, it is less clear whether clinical presentation has returned to baseline levels in subsequent years. Our study aimed to compare the current clinical presentation of melanoma with that in the pre-pandemic setting. Methods: We conducted a retrospective multicenter study involving Italian melanoma referral centers within the SICO network. Patients with a newly diagnosed primary cutaneous melanoma were included in the study and were grouped into four time periods: pre-pandemic (March 2019 to February 2020); pandemic (March 2021 to February 2022); the first post-pandemic year (March 2022 to February 2023); and the second post-pandemic year (March 2023 to February 2024). Our focus was on clinically relevant features at diagnosis, including Breslow thickness, ulceration, stage and sentinel lymph node status. We evaluated differences across periods using regression models that accounted for the multicenter design. Results: A total of 4938 patients were included in the study. Compared with the pre-pandemic period, melanomas diagnosed during and after the pandemic were thicker, more frequently ulcerated and more likely to be in stages II–III. The rate of sentinel lymph node positivity also increased. Notably, these patterns did not normalize over time, remaining evident even in the second post-pandemic year. The results were consistent after adjusting for age and sex. Conclusions: In this large Italian study, melanoma continues to be diagnosed at a later stage than in the pre-pandemic period. This persistent shift may reflect a combination of delayed access to care and ongoing system-level constraints. These findings emphasize the importance of restoring timely access to dermatological evaluation and reinforcing early detection strategies. Full article

Background: Melanoma remains a leading cause of cancer-related mortality, with early detection being the primary determinant of survival. The emergence of MLLMs offers a potential paradigm shift in accessible screening. However, the diagnostic reliability and safety of these general-purpose models in oncology remain insufficiently characterized. Methods: This study performed a head-to-head comparison of GPT-5, Gemini 3, and Grok 4 to evaluate their efficacy as first-level screening tools for cutaneous melanoma. A retrospective analysis was conducted using a balanced dataset of 100 clinical images (50 histopathologically confirmed benign, 50 malignant) from the ISIC archive. Results: Gemini 3 achieved the highest overall accuracy (71%) and specificity (94%), while Grok 4 demonstrated the highest sensitivity (52%). All models exhibited a critical deficit in sensitivity, missing approximately half of the malignant lesions. Statistical testing revealed no significant performance differences between the models (p > 0.05). Notably, Gemini 3 exhibited severe overconfidence, maintaining a high CI (84.62%) even during false-negative predictions, whereas GPT-5 and Grok 4 showed better calibration with a significant drop in confidence upon incorrect diagnosis. Conclusions: While current MLLMs possess a foundational capacity for dermatological analysis, their unacceptably low sensitivity and potential for overconfident misdiagnosis render them unsafe as standalone screening tools. At present, MLLMs should only be utilized as complementary tools under strict clinical supervision. Full article

Background/Objectives: Accurate target delineation is critical in radiotherapy for head and neck non-melanoma skin cancer (NMSC), where tumor depth and subclinical extension are often underestimated by clinical and dermoscopic assessment alone. While high frequency ultrasound has shown value in surface-based radiotherapy techniques, the role of ultra-high frequency ultrasound (UHFUS) within external beam radiotherapy (EBRT) workflows remains poorly defined. Methods: We conducted a single-institution observational feasibility study including all consecutive patients with head and neck NMSC treated with definitive or adjuvant radiotherapy between July 2022 and July 2023 using a structured multidisciplinary workflow integrating pre-treatment UHFUS. UHFUS was systematically performed prior to CT simulation and incorporated into radiotherapy planning. The primary endpoint was the impact of UHFUS on radiotherapy decision-making, predefined as modification of target delineation, treatment intent, or beam modality selection. Secondary endpoints included feasibility, early local control, and late toxicity (descriptive). Results: Thirty patients were included (median age 85 years; range 66–99). UHFUS influenced at least one decision endpoint in 13 patients (43.3%). In the definitive radiotherapy cohort (n = 18), UHFUS modified gross tumor volume delineation in eight patients (44.4%), with an increase in median GTV from 17.5 cm³ to 24.3 cm³. Among patients initially referred for adjuvant radiotherapy (n = 12), UHFUS identified macroscopic residual disease in two cases, leading to a change in treatment intent from adjuvant to definitive radiotherapy. UHFUS supported beam modality selection in three patients by enabling safe use of electron therapy for superficial lesions. After a median follow-up of 24 months (range 12–24), no local recurrences were observed. Late toxicity was limited to grade 1 cutaneous events. Conclusions: Integration of UHFUS into EBRT planning for head and neck NMSC is feasible and clinically informative. UHFUS acts as a decision-shaping tool, influencing target delineation, treatment intent, and modality selection within a multidisciplinary workflow. These findings support further prospective evaluation of UHFUS-guided radiotherapy planning to standardize decision algorithms and assess long-term clinical impact. Full article

Background/Objective: Although most melanocytic lesions are diagnosed as benign or malignant by histopathologic evaluation, with or without the aid of immunohistochemistry, diagnosis may remain uncertain in a minority of cases. Assessment of copy number abnormalities (CNAs) may provide sufficient additional evidence to favor either a benign or malignant diagnosis in both pediatric and adult cases and in melanocytic lesions of various subtypes, including Spitzoid, mucosal, and acral. CNAs are common in melanomas, while they are rare, with few exceptions, in benign lesions. Detection of CNAs by fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA) has been well established for melanocytic lesions, with advantages and disadvantages for each. The objective of this meta-analysis was to evaluate the utility of CNA testing for the diagnosis of melanoma, across subtypes, when a lesion remains ambiguous after histopathologic and immunohistochemical assessment. In addition, the utility of CNAs to determine prognosis in established diagnoses of melanoma was also evaluated. Methods: The Cancer Genomics Consortium Working Group for Melanocytic Lesions reviewed published data from January 1998 through September 2022 of CNAs in melanocytic lesions detected by either FISH or CMA and conducted a meta-analysis of the findings. Results: Specific abnormalities common in primary cutaneous melanomas of various subtypes and uveal melanomas were enumerated. Differences in CNAs found in primary versus metastatic lesions were also determined, and published evidence for prognosis was summarized. Conclusions: The working group established evidence-based recommendations for the use of CNA testing for evaluation of ambiguous melanocytic lesions. Full article

Background/Objectives: The primary objective of this systematic review is to synthesize the available evidence regarding the safety of the various treatment options for advanced uveal melanoma. A thorough understanding of a drug’s safety profile enables early identification and management of adverse reactions, thereby preventing clinical deterioration and minimizing the need for dose reduction, treatment delays, or therapy discontinuation. Methods: In accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR (Assessing the Methodological Quality of Systematic Reviews) guidelines, this review included all clinical studies that examined the most common adverse events associated with all available systemic treatments for metastatic uveal melanoma. Following the study selection process, nine studies were considered eligible and were included in the review. Results: Treatment with the bispecific antibody was associated with a favorable toxicity profile. The most severe adverse event observed was limited to cutaneous toxicity. Analysis of treatment-related adverse events (TRAEs) of grade ≥3 showed that patient cohorts receiving trametinib, selumetinib, and darovasertib experienced the lowest incidence of severe events (with the exception of creatine phosphokinase elevation observed with selumetinib), suggesting a comparatively more favorable safety profile for these agents. At present, the most robust efficacy data in the metastatic uveal melanoma setting are available for tebentafusp and darovasertib. Conclusions: This study provides the most comprehensive analysis of TRAEs in randomized trials of UM, delineating the toxicity and safety profiles of current therapies to guide personalized treatment decisions. Full article

Background: Although blinded independent central review (BICR) can reduce assessment variability, it introduces additional financial and logistical burdens to trial operations. This study analyzed the discrepancy indexes (DIs) to evaluate differences between progression-free survival (PFS) assessments by local investigators (LIs) and BICR in randomized clinical trials (RCTs) of patients with metastatic melanoma. Methods: A comprehensive literature search was conducted on PubMed, Embase, and Cochrane databases up to 30 June 2024. The primary outcome was the DI, which was calculated for each trial as a ratio of the hazard ratios (HR)_BICR by HR_LI. The agreement between PFS HRs was also evaluated using the intraclass correlation coefficient (ICC) and Pearson’s correlation coefficient (r). Results: Twelve studies comprising 4915 patients were included in this study. Of these, 10 (83%) were Phase III, 11 (92%) were cutaneous melanoma, one was uveal, and all identified PFS as the primary endpoint. Most (86%) of the PFS comparisons yielded the same statistical inference by both BICR and LIs. The overall combined DI was calculated at 1.08 (95% CI: 1.01–1.15), indicating a statistically significant, numerically small difference in PFS evaluations driven primarily by the uveal Phase III double-blinded study, while there was a strong overall correlation [(ICC: 0.87, p < 0.001); (r = 0.89, 95% CI 0.67–0.96, p < 0.0001)]. Cutaneous melanoma trials demonstrated strong agreement between BICR and local investigator assessments. Conclusions: In randomized trials of metastatic cutaneous melanoma, LI-assessed PFS closely aligns with BICR and provides equivalent trial-level conclusions in most cases. These findings support the use of LI-assessed PFS as a valid and practical primary endpoint, without routine requirement for BICR. Central review should be reserved for selected scenarios. Full article

Background/Objectives: Malignant melanoma is a highly aggressive cancer associated with significant mortality, underscoring the need for continued research efforts. COMBI-EU (NCT03944356) is a prospective, non-interventional study that aims to assess adjuvant dabrafenib and trametinib usage in clinical practice, the impact of AE management, and the usage of app-based documentation on treatment adherence. Methods: Adults with complete surgical resection of stage III BRAF V600-mutant cutaneous melanoma were included. The primary endpoint was median time on treatment (TOT). Adverse event (AE) management was classified as either a high or low level of management. The rating of AE management based on a self-developed algorithm and rules from COMBI-APlus was used to analyze the impact of AE management on TOT. App-based documentation of medication intake and patient-reported outcomes (CANKADO PRO-React; version 6.0, 06.03.2019) was offered. Results: For 225 patients, the median TOT was 11.8 months (95% confidence interval [CI]: 11.7, 12.0). Treatment was completed by 138 patients (61.3%); 37 (16.4%) discontinued due to treatment-related AEs (TRAEs). TRAEs (≥1) were experienced by 181 patients (80.4%); the most common was pyrexia (38.2%). High-level AE management showed a trend toward improved treatment adherence (high versus low level: hazard ratio [HR]: 0.74; 95% CI: 0.49, 1.14); this improvement was significant with pyrexia management (HR: 0.52; 95% CI: 0.29, 0.93). Seventy-nine (35%) and 33 patients (15%) intended to use and eventually used the app, respectively. A similar proportion of patients remained on treatment for 12 months irrespective of app usage (use, 39.4% vs. non-use, 36.5%). Conclusions: High-level TRAE management showed a trend toward improved treatment adherence, which was statistically significant for pyrexia. Optional use of an app did not influence treatment adherence. Full article

Background: The COVID-19 pandemic disrupted access to routine dermatologic care and may have delayed melanoma diagnosis and management. Evidence on the post-pandemic period and on hospital-based referral cohorts remains limited. We assessed melanoma presentations before, during and after the pandemic in three skin cancer centers in North Rhine-Westphalia, Germany. Methods: We conducted a multicenter retrospective cohort study of inpatients with cutaneous melanoma grouped into Phase 1 (February 2017–February 2020), Phase 2 (March 2020–March 2023), and Phase 3 (April 2023–May 2024). The primary endpoint was Breslow tumor thickness (TT) among invasive melanomas, analyzed using multivariable log-linear regression adjusted for center, age, sex, anatomic site, and histologic subtype. Secondary endpoints included T category and AJCC stage distributions (including stage 0/Tis), macroscopic primary tumor specimen dimensions (area and volume; available cases), staging work-up and sentinel lymph node biopsy (SLNB) indicators, and exploratory laboratory parameters (LDH, S100, CRP) and dermal mitotic rate. Results: We included 2960 patients (Phase 1: 1162; Phase 2: 1251; Phase 3: 547). Median TT among invasive melanomas was 1.1 mm (IQR 0.6–2.3), 1.1 mm (0.5–2.4), and 1.0 mm (0.5–2.3) across phases (p = 0.037). In adjusted models among invasive tumors, TT did not increase (Phase 2 vs. Phase 1: 0.97, 95% CI 0.90–1.04; Phase 3 vs. Phase 1: 0.94, 0.86–1.03). AJCC stage 0 decreased from 7.7% and 6.1% to 2.0%; adjusted OR Phase 3 vs. Phase 1: 0.24 (95% CI 0.13–0.46). Within invasive tumors, the distribution of T categories (T1a–T4) and AJCC stages I–IV was similar across periods. Among cases with available macroscopic primary tumor specimen dimensions, median area and volume were higher during and after the pandemic (area p = 0.030; volume p = 0.042), but period effects attenuated in models adjusted for TT. Exploratory analyses suggested a higher proportion of elevated LDH and a lower proportion of elevated S100 across periods, while CRP and dermal mitotic rate showed no clear period shift. Conclusions: In this large melanoma inpatient cohort, the pandemic period was not associated with thicker invasive melanomas after covariate adjustment. However, a persistent reduction in stage 0/Tis presentations in the post-pandemic period suggests ongoing disruption or shifting of early detection and referral pathways. Exploratory increases in macroscopic tumor dimensions may point to changes not captured by thickness alone, but require cautious interpretation given missingness and potential documentation effects. Full article