Search Results (1,828)

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine malignancy. Like cutaneous malignant melanomas, a subset of MCCs can clinically present without an identifiable primary tumour, termed Merkel cell carcinoma of unknown primary (UPMCC), with incompletely understood behaviour and prognosis. Our objectives are to evaluate the clinical presentation, management and survival outcomes in UPMCC and compare overall survival with metastatic MCC of known-primary origin. Methods: A retrospective review of 252 consecutive MCC patients (1992–2023) identified 20 cases of histologically confirmed nodal or metastatic UPMCC. Demographics, anatomical distribution, treatment and oncological outcomes were analysed. Overall survival was compared with patients presenting with metastatic MCC of known primary. Results: The cohort included 15 males and 5 females (mean age 76 years). Presentation most commonly involved inguinal (n = 7) and axillary (n = 6) nodes, followed by parotid and cervical basins (n = 4). Management was multimodal, including lymphadenectomy, radiotherapy and systemic therapy. Six patients remained disease-free at a mean follow-up of 63.3 months. The mean overall survival was 43.65 months for UPMCC versus 39.29 months for known-primary metastatic MCC. Conclusions: UPMCC most commonly presents as inguinal or axillary nodal disease. Survival outcomes suggest a trend toward improved prognosis compared to known-primary metastatic MCC. Full article

Immunity plays critical roles in cutaneous melanoma. We investigated the association between the pro-inflammatory interleukin-1β gene (IL-1B) rs16944 (-511 C > T) promoter single nucleotide polymorphism (SNP) and cutaneous melanoma susceptibility and clinical features. This observational case–control study included 133 patients with cutaneous melanoma and 900 healthy controls from Northeastern Italy. The rs16944 C > T polymorphism was determined by genomic DNA restriction fragment analysis. The IL-1B rs16944 C allele (OR = 1.44, p = 0.014) and CC genotype (OR = 1.48, p = 0.037) were associated with modestly higher odds of melanoma. Among melanoma patients, the CC genotype was associated with Stage I disease (OR = 2.45, p = 0.016) and Breslow thickness ≤ 0.75 mm (OR = 2.27, p = 0.049), whereas it was less frequent in Stage IV melanoma (OR = 0.37, p = 0.029). The CT genotype was associated with Stage IV melanoma (OR = 3.03, p = 0.014) and with lower-limb (OR = 2.45, p = 0.038) and lower-extremity (OR = 3.09, p = 0.005) melanoma. These divergent associations are exploratory and do not establish disease trajectory or a functional effect of rs16944; mechanistic interpretation remains uncertain because IL-1β expression or activity was not measured in this cohort. To our knowledge, this is the first report of an association between a genetic polymorphism and lower-limb/lower-extremity melanoma. These exploratory findings require confirmation in independent cohorts. Full article

Background/Aim: Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase involved in cell growth, proliferation, and angiogenesis. While FGFR1–3 are well studied in cancer, FGFR4 remains relatively understudied, and the distribution of its mutations across cancers and patient populations is not well defined. Materials and Methods: A retrospective pan-cancer analysis was performed using the AACR Project GENIE v12 database via cBioPortal. Tumors with somatic FGFR4 mutations were included, excluding copy number alterations and structural variants. Mutations were grouped by hotspot (amino acid 401) and major protein domains. Comparative analyses assessed cancer type distribution, demographics, mutation burden, and co-occurring genomic alterations using chi-square testing with multiple comparison correction. Results: A total of 4565 tumor samples (4283 patients) were analyzed. FGFR4 alterations were observed across diverse malignancies, most commonly non-small cell lung cancer, colorectal cancer, and melanoma. Mutations clustered primarily in the tyrosine kinase and immunoglobulin I-set domains, with no significant variation in distribution across cancer types. Sex was not associated with the mutation group, while race and ethnicity showed significant differences. The FGFR4 hotspot 401 group demonstrated a higher mutation burden, driven by a subset of hypermutated tumors, and showed enrichment for co-occurring alterations in chromatin remodeling, DNA repair, tumor suppressor, and receptor tyrosine kinase genes; however, sensitivity analyses indicated this association was largely attributable to mutation burden rather than a mutation-specific effect. Domain-based mutation groups had lower mutation burdens and fewer co-alterations. Conclusions: FGFR4 alterations occur across a broad range of cancers with consistent domain-level patterns. The hotspot 401 mutation shows a higher mutation burden and co-alteration frequency driven largely by a subset of hypermutated tumors, rather than acting as an isolated driver. Full article

Melanoma is a highly aggressive malignancy characterized by strong invasive and metastatic potential. CPEB4 has been implicated in melanoma progression and may serve as a potential therapeutic target. Alkannin has previously been reported to exert antitumor activity against melanoma; however, its in vivo efficacy and direct molecular interaction with CPEB4 remain unclear. In this study, a subcutaneous xenograft model using BALB/c nude mice was used to assess the in vivo antitumor effects of alkannin, and CPEB4 expression was analyzed via Western blotting. DARTS, CETSA, and SPR investigations were used to elucidate the interaction between alkannin and CPEB4. In addition, stable CPEB4-knockdown A375 melanoma cells were established to examine the effects of alkannin on cell proliferation, apoptosis, cell cycle progression, migration, invasion, and downstream signaling molecules. Alkannin markedly suppressed tumor growth in the xenograft model and reduced CPEB4 expression in a dose-dependent manner compared with the model group. DARTS and CETSA demonstrated alkannin-induced stabilization of CPEB4, while SPR analysis using purified recombinant CPEB4 showed a direct physical interaction with alkannin, with micromolar affinity. At the molecular level, alkannin downregulated CPEB4 and PRC1 expression (p < 0.05), whereas CPEB4 knockdown markedly suppressed MITF and PRC1 (p < 0.05). Notably, alkannin treatment alone did not significantly alter MITF protein expression under the present experimental conditions. Alkannin exerts antitumor activity against melanoma, while its interaction with CPEB4 and the associated molecular changes may contribute to cellular responses involving proliferation, survival, migration, invasion-related phenotypes, and mitotic regulation. Full article

Malignant melanoma is characterized by high metastatic potential and cellular plasticity. Its progression is driven not only by genetic alterations but also by epigenetic reprogramming and changes in the transcriptome, mediated by transcription factors. The AP-1 family favors an invasive cell state by facilitating processes such as angiogenesis and migration. However, the AP-1-driven regulatory landscape and its implications for melanoma plasticity remain poorly understood. Here, we further elucidate the role of the AP-1 members c-Jun and Fra-1 in enhancer-related gene regulation during melanoma development. Integrative ChIP-seq and RNA-seq analyses revealed extensive enhancer reprogramming during tumor formation and significant upregulation of genes annotated to enhancers gained in melanoma cells. On average, half of these regions are directly bound by c-Jun/Fra-1, given a high AP-1 motif rate (~80%) and chromatin accessibility. Genes associated with c-Jun/Fra-1-bound enhancer regions are functionally linked to an invasive phenotype and comprise well-known melanoma drivers involved in migration and EMT. Clinically, high c-Jun/Fra-1 and target gene expression correlate with poor survival in BRAF wild-type and NRAS mutant melanoma patients, highlighting c-Jun/Fra-1 as a potential biomarker and therapeutic target. Overall, our data identify c-Jun/Fra-1 as important contributors to melanoma development through enhancer-mediated transcriptional programs. Full article

Photodynamic therapy (PDT) is a cornerstone non-invasive modality for keratinocytic precancers and non-melanoma skin cancer (NMSC), leveraging selective photosensitizer accumulation, light activation, and reactive oxygen species (ROS) generation. This narrative review synthesized literature from major databases (2010–2025) to comprehensively evaluate PDT’s molecular mechanisms, innovative optimization protocols, and clinical efficacy across actinic keratosis (AK), field cancerization, Bowen’s disease (BD), basal cell carcinoma (BCC), and invasive squamous cell carcinoma (cSCC). The evidence highlights frontline clinical maturity and excellent cosmetic outcomes for superficial lesions (AK, field cancerization, superficial BCC, and BD), with daylight PDT offering a virtually painless alternative for widespread dysplasia. However, therapeutic reliability decreases in thick nodular, pigmented, or high-risk lesions due to optical barriers and tissue hypoxia. To overcome these limitations, advanced physical and chemical enhancements—such as ablative fractional lasers, iron chelators, epigenetically enhanced PDT (ePDT), and targeted nanocarriers—are actively reshaping drug delivery and cellular susceptibility. Furthermore, cyclic PDT serves as an indispensable tissue-sparing intervention for organ transplant recipients and Gorlin syndrome patients. In conclusion, while PDT is highly effective for superficial neoplasias, precise histopathological stratification and the integration of nanomedicine are critical to overcoming current biological barriers in aggressive dermatological malignancies. Full article

Background/Objectives: Thymidylate synthase (TYMS) represents an important therapeutic target. Methods: In this study, TYMS expression was analyzed by immunohistochemistry on a tissue microarray containing 17,371 samples from 136 different tumor types. Results: TYMS staining was seen in 42.9% of 15,361 analyzable tumors, with weak staining in 35.4%, moderate in 5.7%, and strong in 1.8%. TYMS occurred in at least one case of 127 categories, of which 71 showed TYMS staining in at least 50% of cases, and 56 included at least one case with strong positivity. TYMS positivity occurred most commonly in lymphomas (81.3–96.5%), sarcomas and sarcomatoid carcinomas (33.3–100%), malignant melanoma (70.5–90.7%), cervical adenocarcinoma (78.3%), and squamous cell carcinomas of various sites (57.1–77.9%). High TYMS expression was linked to advanced pT (p = 0.0097), high grade (p < 0.0001), ER negativity (p < 0.0001), and PR negativity (p = 0.0002) in invasive breast cancer of no special type; high grade (p < 0.0050), high UICC stage (p = 0.0060), and nodal metastasis (p = 0.0120) in clear cell renal cell carcinoma (RCC); high grade (p < 0.05) and nodal metastasis (p = 0.0045) in papillary RCC; high Gleason grade (p < 0.0001) and advanced pT stage (p = 0.0149) in prostatic adenocarcinoma; high pT (p < 0.0001), nodal metastasis (p = 0.005), lymphatic (p = 0.0064) and venous invasion (p = 0.0005), left side location (p < 0.0001), and microsatellite instability (p < 0.0001) in colorectal adenocarcinoma; and high grade (p < 0.0001) in squamous cell carcinomas of different sites. Conclusions: TYMS is often overexpressed across different cancer entities and shows associations with several adverse histopathological parameters commonly used to describe tumor phenotypes. Full article

Background: Uveal melanoma (UM) represents the most prevalent primary intraocular malignancy in adults, yet patients harboring GNAQ/GNA11 mutations face particularly poor prognoses with median survival of merely 6–12 months following metastasis. Multi-targeted combination therapy offers a promising strategy to circumvent drug resistance. The present study investigated the synergistic anti-tumor efficacy and mechanistic basis of Isoliquiritigenin (ISL), Quercetin (Que) and Methylnissolin (Meth), three bioactive constituents from Astragalus membranaceus (Huangqi, a widely used traditional Chinese medicinal herb) against UM. Methods: Molecular docking and 100 ns molecular dynamics simulations assessed binding stability between the compounds and their respective targets (Gαq, MEK and YAP). Synergistic interactions were quantified using the Zero Interaction Potency (ZIP) model, a reference synergy model that compares observed combination effects to predicted non-interaction baselines across full dose–response matrices, based on CCK-8 assays. Cell cycle distribution, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry. Western blotting detected target proteins and apoptotic markers. A male BALB/c nude mouse xenograft model validated therapeutic efficacy and systemic safety. Results: Molecular docking revealed binding energies <−7.0 kcal·mol⁻¹ for all three drug–target pairs, with molecular dynamics trajectories confirming stable complex conformations (RMSD < 3 Å). In vitro, the ISL-Que-Meth (IQM) combination exhibited strong synergism (ZIP scores > 10), significantly increasing apoptotic rates, collapsing mitochondrial membrane potential and upregulating cleaved-caspase 9 expression compared with monotherapy, and a modest G2/M phase accumulation was also observed, although the magnitude was limited relative to apoptotic induction. In vivo, the triple combination achieved approximately 50% reduction in tumor growth compared with the control group, with effects comparable to or exceeding those of the clinical reference agent Trametinib, and reduced Ki67 proliferation indices while elevating cleaved-caspase 9 levels, without eliciting hepatorenal toxicity. While these data demonstrate therapeutic efficacy, they do not establish in vivo synergy, as single-agent and dual-combination arms were not included in the xenograft design. Conclusions: These findings demonstrate that IQM synergistically suppresses UM growth in association with coordinated modulation of Gαq/MEK/YAP axis components and caspase 9-dependent apoptosis via the intrinsic mitochondrial pathway, providing preclinical evidence for natural product-based multi-targeted therapy against UM. Full article

Background/Objectives: Metastases from cutaneous malignancies to the female genital tract and pelvic lymph nodes are rare clinical entities that frequently masquerade as primary gynecologic tumors, leading to significant diagnostic challenges. The distinction between primary and metastatic disease is critical, yet complex, given the varying patterns of spread exhibited by different skin cancers. This study aims to provide a tumor-specific overview of these metastatic patterns to guide diagnosis and therapy. Methods: We conducted a narrative review informed by a systematic literature search of MEDLINE/PubMed, Embase, Scopus, and Web of Science for records regarding primary cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), and cutaneous lymphomas metastasizing to the female genital tract (FGT) or pelvic lymph nodes. Data were synthesized qualitatively to identify organotropic patterns, diagnostic pitfalls, and management outcomes across these distinct malignancies. Results: The analysis reveals distinct metastatic niches: cutaneous melanoma shows a predilection for the ovary, often mimicking epithelial ovarian carcinoma, whereas cSCC and MCC typically involve pelvic lymph nodes via contiguous spread from inguinal basins. Histologic evaluation with broad immunohistochemical panels is mandatory to confirm the diagnosis, as imaging alone lacks specificity. Crucially, the introduction of immune checkpoint inhibitors and targeted therapies has significantly improved survival in advanced melanoma, cSCC, and MCC, altering the role of pelvic surgery. Conclusions: Management of cutaneous malignancies metastatic to the pelvis is shifting from a focus on radical surgery to a systemic-first approach. Pelvic metastasectomy should be reserved for selected oligometastatic cases or symptom control within a multidisciplinary framework. Clinicians must maintain a high index of suspicion in patients with a history of skin cancer to avoid overtreatment and optimize quality of life. Full article

Background/Objectives: Differences among scanners and reconstruction methods may limit the comparability of quantitative metrics derived from fluorodeoxyglucose positron emission tomography (FDG PET)/computed tomography (CT). Although harmonization reduces inter-scanner variability in standardized uptake values (SUVs), its impact on the preservation of lesion-level ranking in real-world clinical datasets remains unclear. Here, we evaluated the robustness of PET quantitative metrics, particularly focusing on rank preservation after harmonization. Methods: Phantom and clinical data retrospectively acquired from three institutions using four PET/CT scanner types were analyzed. Harmonization parameters were derived from National Electrical Manufacturers Association IEC Body Phantom data, using the oldest scanner as the reference, and were directly applied to the clinical datasets. Clinical evaluation included head and neck malignant melanoma (HNMM; high FDG avidity) and adenoid cystic carcinoma (ACC; low FDG avidity). Rank preservation between pre- and post-harmonization values was assessed using Spearman’s rank correlation coefficient (ρ). Results: Phantom-based harmonization reduced inter-scanner differences and enabled consistent evaluation in clinical datasets (HNMM: 34 patients, 93 lesions; ACC: 18 patients, 38 lesions). SUVpeak demonstrated the highest rank preservation across tumor types and lesion sizes (ρ = 0.94–1.00). Metabolic tumor volume (MTV) showed a high rank correlation in HNMM with an absolute threshold (MTV2.5; ρ = 0.99), but robustness varied depending on threshold definition, tumor type, and lesion size. Tumor-to-liver ratios showed moderate rank preservation. Conclusions: Our results suggested that SUVpeak is the most robust preservation of lesion ranking across tumor types after harmonization, suggesting its suitability as a reliable imaging biomarker in multicenter studies. Meanwhile, careful standardization is needed when using MTV-based metrics for prognostic evaluation. Full article

Background and Clinical Significance: Malignant melanoma with primary or metastatic intestinal involvement is a rare entity, often diagnosed late and associated with severe complications such as bowel obstruction and perforation. Differential diagnosis of primary intestinal lymphoma may be challenging in the absence of an identifiable primary lesion. Case Presentation: We report the case of a 35-year-old male with no significant medical history who was admitted for persistent abdominal symptoms. Contrast-enhanced abdominal CT revealed a giant circumferential jejunal mass (109/147/156 mm) causing marked luminal stenosis and mesenteric lymphadenopathy, initially raising suspicion of primary intestinal lymphoma. The patient subsequently developed upper intestinal obstruction and severe anemia (Hb 5.5 g/dL), requiring an emergency exploratory laparotomy. Intraoperatively, a voluminous unresectable tumor extending to the mesenteric root was identified, and a feeding jejunostomy was performed. The postoperative course was complicated by tumor perforation and generalized peritonitis, necessitating reoperation. Histopathological examination established the diagnosis of malignant melanoma, with no identifiable primary site, which is most consistent with metastatic melanoma (MUP). PET-CT staging demonstrated metastatic disease (mesenteric, retroperitoneal and supraclavicular lymph nodes, as well as subcutaneous nodules), consistent with a stage IV disease. Molecular analysis revealed a BRAF V600E mutation. Combined immunotherapy (Nivolumab + Ipilimumab) was initiated, resulting in a partial radiological response after three cycles. Conclusions: Intestinal involvement by malignant melanoma might mimic other gastrointestinal malignancies and be the cause of a delayed diagnosis and severe surgical complications. Multidisciplinary management is essential, and modern immunotherapy offers promising outcomes even in advanced-stage disease. Full article

In patients with advanced or metastatic melanoma, BRAF mutation assessment is routinely performed to identify patients who may benefit from BRAF-targeted therapy. This study aimed to assess the role of BRAF mutation status in relation to histopathological characteristics and survival of patients with stage II and III malignant melanoma. A prospective cohort of 108 patients with pT3 malignant melanoma who were treated in a comprehensive cancer center were included in the analysis. All patients were treated according to contemporary melanoma management guidelines between 2016 and 2024, with a minimum follow-up of 12 months extending to 2025. Overall survival (OS) and progression-free survival (PFS) analyses were performed in the study cohort. The study included 108 patients with stage II–III malignant melanoma, with a mean age of 56.73 ± 13.51 years. Superficial spreading melanoma was the most frequent histological subtype, followed by nodular and acral melanoma. Most tumors were classified as Clark level IV, with a median Breslow thickness of 3 mm, and ulceration was present in the majority of cases. Lymph node involvement was observed in over half of the patients, and BRAF mutations were identified in 56.48% of cases (the most common variant was V600E). Brisk tumor-infiltrating lymphocytes were significantly more frequent in BRAF wild-type tumors compared with BRAF-mutant tumors. When assessing associations with survival, BRAF mutation status was not found to be an independent predictor. In the multivariate Cox model, TIL status was associated with improved OS (HR 3.33, 95% CI 1.41–7.88, p = 0.006). In addition, in the multivariate analysis, TIL status was also associated with improved PFS (HR 5.23, 95% CI 2.22–12.3, p < 0.001). BRAF wild-type tumors were significantly more likely to exhibit a brisk infiltrate. BRAF mutation status was not found to be an independent predictor of survival. TIL status remained significantly associated with OS and PFS in multivariable analysis. Full article

Melanoma incidence is steadily on the rise but widespread prevention awareness and novel treatment approaches have substantially ameliorated the prognosis of the disease. Microphthalmia-associated transcription factor (MITF) is an essential transcription factor that plays a central role in the transcriptional circuitry of both normal melanocytes and malignant melanoma. Since over 30 years have elapsed since its discovery in mice, a large number of its target genes have been identified in pigment cells. Many upstream regulators of MITF have also been identified. Despite these substantial discoveries, MITF function, especially in melanomas, still remains elusive in several aspects. MITF is absolutely required for melanin formation because it transcribes virtually all genes required for the synthesis, storage, and transport of the pigment. Importantly, MITF is necessary for prevention of apoptosis in melanomas, at least at the early stages. However, in some metastases, MITF may be absent in most cells and its antiapoptotic function is evidently replaced by other proteins that not yet been fully identified. Furthermore, MITF is a specific nevus and melanoma marker, which is routinely used in immunohistochemistry, along with other markers, to distinguish pigmented and other skin lesions. In melanomas, high-MITF melanoma cell subpopulations are considered differentiated, i.e., pigmented and rapidly proliferating. In contrast, low-MITF cells proliferate slowly but are invasive with cancer stem cell-like properties. Although MITF activates mostly antiapoptotic and pro-proliferative genes, it also activates typical cell cycle inhibitors such as the p16 and p21 proteins. Here we discuss the issues of MITF multifunctionality in melanoma and associated research prospects. Full article

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Background: Melanoma incidence is rising rapidly worldwide and stands out due to its high lethality. Despite advances in clinical treatment and in understanding melanoma-sensitive genes and molecular pathogenesis, a specific area of ongoing research is the connection between stress-related β-adrenergic receptors (ARs), hypoxia, and neovascularization in melanoma tumor progression. This exploratory study aimed to investigate the expression of β3-AR, HIF-1α, and CD31 in several cellular subsets of atypical melanocytic lesions and their interplay in promoting melanoma malignancy. Methods: Twenty-seven patients with melanocytic lesions at different stages that were surgically removed were retrospectively selected; clinical-pathological and dermoscopic data were collected. Results: Immunohistochemical and digital evaluation revealed a significant upregulation of β3-AR in malignant melanoma melanocytes and in macrophages from invasive >pT1a melanomas compared to dysplastic nevi. Increased HIF-1α expression in malignant melanocytes and CD31 expression levels in >pT1a melanomas were observed. Ulcerated lesions exhibited a higher percentage of β3-AR, HIF-1α, and CD31 expression. Pearson correlation analysis revealed positive associations among these markers in human malignant melanoma, suggesting a potential relationship between adrenergic signaling, hypoxia, and tumor vascularization. Conclusions: These exploratory findings suggest that β3-AR, HIF-1α, and CD31 may represent interconnected components of the melanoma microenvironment. Unraveling these interactions in larger, independent cohorts and functional studies may provide additional insights into melanoma biology and help define their potential translational relevance. Full article