Recently, dolichol phosphate mannose synthase (DPMS) has emerged as a promising new target for treatment in various cancers. Nonetheless, DPM2, a crucial element of the DPMS family, remains unexplored in melanoma research. This study aims to explore the predictive significance and biological role of DPM2, utilizing extensive databases and functional tests conducted in vitro. We conducted an in-depth examination of the DPM2 expression feature within The Cancer Genome Atlas database. Group differences were evaluated using Student's t-test, one-way analysis of variance, and long-rank test, while survival distributions were estimated using the Kaplan-Meier method. Functional experiments were conducted in multiple melanoma cell lines to evaluate the effects of altered DPM2 expression. Our research indicated a direct correlation between the expression levels of DPM2 and the severity of melanoma. In addition, an elevated level of DPM2 expression was significantly linked to unfavorable prognoses. Suppression of DPM2 inhibits the proliferation, migration, and invasion of melanoma cells and induces their apoptosis. These findings suggest that DPM2 plays a pivotal role in melanoma progression and may serve as an independent prognostic biomarker for the disease.
Combined B-Raf proto-oncogene, serine/threonine kinase/MAPK kinase (BRAF/MEK) inhibition, along with immune checkpoint inhibition, has significantly improved the outcomes of patients with advanced melanoma harboring BRAF V600 mutations. However, the clinical efficacy of targeted therapy for melanomas with rare class II BRAF mutations, such as L597R, remains unclear. We report two patients with metastatic BRAF L597R-mutated melanoma who responded to BRAF/MEK inhibition. Both patients initially underwent dual immune checkpoint inhibition. Because of rapid clinical deterioration and disease progression, the treatment was switched to binimetinib in case 1 and binimetinib/encorafenib combination therapy in case 2. Both patients demonstrated a rapid clinical response to targeted therapy, including a notable reduction in the tumor burden and symptomatic improvement. In case 1, resistance developed after 3 months, resulting in disease progression. In case 2, targeted therapy was discontinued after 8 weeks because of the anticipated emergence of resistance, and immune checkpoint inhibition was reinitiated. Stable disease and symptom control were maintained for an additional 6 months, after which disease progression was observed. The overall survival rates were 10 and 11 months, respectively. These cases illustrate that targeted therapy can induce a rapid response in patients with metastatic melanoma harboring the BRAF L597R mutation while also highlighting the risk of early treatment resistance. This treatment option should be considered, particularly for patients with pronounced symptoms and high tumor burden.
Melanoma is an aggressive skin cancer with a rising incidence, posing clinical challenges because of limited prognostic tools and therapeutic resistance. Over recent years, neutrophil extracellular traps (NETs) have gained increasing attention in cancer biology for their role in tumor progression and immune modulation across various malignancies. The role of NETs in the progression of melanoma remains unclear. This study aimed to construct a NET-related prognostic model and elucidate the functional role of the key gene dedicator of cytokinesis 2 (DOCK2) in the pathogenesis of melanoma. We integrated bulk RNA sequencing data from The Cancer Genome Atlas, the Genotype-Tissue Expression project, and the Gene Expression Omnibus, along with single-cell RNA sequencing data. A set of NET-related differentially expressed genes (NETRDEGs) was identified and proven to be enriched in immune-related pathways. A prognostic risk model based on NETRDEGs accurately predicted 1-, 3-, and 5-year survival (area under the curve > 0.7), with high-risk patients having worse outcomes. DOCK2 was identified as an overexpressed biomarker associated with a favorable prognosis and drug sensitivity. Low DOCK2 expression correlated with a higher tumor mutation burden and increased drug resistance. At the single-cell level, NETRG-associated transcriptional enrichment was prominent in macrophages; we characterized this heterogeneity and identified five novel subclusters. Analysis revealed a critical link between NETs and melanoma, identified a 235-gene NET signature, and established DOCK2 as a prognostic marker associated with the immune microenvironment. Furthermore, the expression of DOCK2 was correlated with the immune microenvironment and drug sensitivity, suggesting that targeting NET pathways could provide novel treatment strategies for melanoma.
Rapid treatment of melanoma is essential to obtain the best possible survival rate, in an epidemiological context that makes access to dermatological care difficult. Tele-expertise (TLE) has rapidly become the most widely practiced form of telemedicine in the world. Since September 2022, TLE has been used in our center. Our objective was to compare the diagnosis time for suspicious pigmented lesions using TLE compared with the classic addressing method (CAM) from September 2022 to December 2023. Two groups were formed based on anatomopathological diagnoses: one group referred through TLE, and the other through CAM. The median delay between the date of consultation request and the date of medical care was assessed in number of days. A total of 160 patients were analyzed. A significant reduction in median diagnosis time was achieved in the TLE group, with a median delay of 23 versus 49 days in the CAM group for all lesions and of 10 versus 28 days for invasive melanomas. The quality of TLE requests was predominantly considered ‘good’ or ‘very good’ quality. TLE could be a key solution to the demographic challenges facing dermatology.
Chemokine and chemokine receptors (CKRs) regulate cell growth, tumor immunity, migration, angiogenesis, and metastasis. We evaluated associations of inherited chemokine/CKR variants with subsequent primary melanomas among patients with a previous melanoma. Our population-based cohort included 2458 incident single primary and 1205 multiple primary melanoma (MPM) cases. We examined 215 a priori candidate polymorphisms selected based on prior evidence and predicted functional relevance, along with nine haplotype blocks. Logistic regression estimated odds ratios and 95% confidence intervals, adjusting for age at diagnosis, sex, age-by-sex interaction, and study center. Thirty variants across 14 genes were nominally associated with MPM ( P < 0.05), with effect sizes ranging from 16 to 80%. Five haplotypes in CXCL12 , CCL18 , CXCR2 , and CCR9 were significantly associated with MPM ( Pglobal < 0.03) with stronger effects than individual-effect alleles. Functional annotation identified 160 associated index variants and linkage disequilibrium proxies acting as skin expression quantitative trait loci for CXCR2 , XCR1 , BCL9L , FYCO1 , PNKD , RUFY4 , and RP11-378A13.1 ( P < 1.06E-05 to 4.3E-34). These variants were classified functionally as candidate causal variants based on convergent regulatory annotation and skin‑specific expression quantitative trait locus evidence, linking chemokine/CKR variants and haplotypes to downstream genes involved in epithelial-mesenchymal-like transition, matrix remodeling, and other tumorigenic processes, thereby implicating immune regulatory mechanisms in melanoma development. To the best of our knowledge, this is the first study to demonstrate an association of a priori chemokine/CKR variants with subsequent melanoma risk. Validation and evaluation of associations with tumor characteristics and survival are warranted.
Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life-threatening hyperinflammatory syndrome characterized by uncontrolled immune activation and cytokine release. Secondary HLH has increasingly been reported in association with modern oncologic therapies, including immune checkpoint inhibitors and targeted therapies for malignant melanoma. Sequential treatment with checkpoint inhibitors followed by BRAF/MEK inhibitors may further increase the risk of immune dysregulation. We report the case of a 61-year-old female with BRAF V600K-mutant metastatic melanoma (stage IV) initially treated with combination immunotherapy consisting of nivolumab and ipilimumab, followed by nivolumab monotherapy. Due to progressive disease and immune-related hypophysitis, targeted therapy with dabrafenib and trametinib was initiated. Shortly thereafter, the patient was admitted with suspected sepsis, gastroenteritis, and a trunk-predominant rash. During hospitalization, she developed hemolysis, disseminated intravascular coagulation, and acute kidney injury. Further evaluation revealed reactivation of Epstein-Barr virus, absolute lymphocytosis, and marked T-cell activation on flow cytometry. An HScore of 234 indicated a 98% probability of HLH. Under supportive treatment and immunosuppressive therapy, inflammatory markers, coagulation parameters, and renal function gradually improved. During the clinical course, the patient developed transient visual disturbances. Neuroimaging excluded cerebral ischemia, and findings were compatible with posterior reversible encephalopathy syndrome, likely secondary to HLH. Visual symptoms resolved within 2 days. This case highlights HLH as a rare but severe complication in patients receiving sequential immune checkpoint inhibition and BRAF/MEK-targeted therapy for metastatic melanoma. Early recognition of hyperinflammatory syndromes and interdisciplinary management are essential to improve clinical outcomes.
Cutaneous head and neck melanoma (CHNM) accounts for a disproportionate share of melanoma-related mortality, yet the prognostic value of its precise anatomical site remains uncertain. We retrospectively reviewed 105 patients with CHNM diagnosed at Chonnam National University Hwasun Hospital between 2002 and 2023. Variables were compared across four sites (scalp, face, neck, ear), and overall survival (OS), melanoma-specific survival (MSS), and recurrence-free interval (RFI) were analyzed using Kaplan-Meier methods and multivariable Cox proportional hazards models. Scalp melanomas arose in younger patients yet displayed the greatest Breslow thickness. Distant metastasis occurred during follow-up in 67% of scalp and 64% of all nonfacial melanomas, compared with 19% of facial melanomas. By Kaplan-Meier analysis, OS and MSS did not differ significantly by anatomic site (log-rank P = 0.18 and P = 0.11), whereas RFI differed across subsites (log-rank P < 0.001), with lower RFI for scalp than face in multiplicity-adjusted pairwise comparisons (adjusted P = 0.002). In multivariable Cox models, Breslow thickness remained independently associated with poorer OS [hazard ratio: 1.457, 95% confidence interval (CI): 1.235-1.719, P < 0.001), MSS (hazard ratio: 1.700, 95% CI: 1.414-2.045, P < 0.001), and RFI (hazard ratio: 1.195, 95% CI: 1.087-1.329, P < 0.001). Overall, scalp melanomas presented with the greatest Breslow thickness and higher metastatic burden, whereas Breslow thickness remained the primary independent prognostic factor for MSS and RFI in Korean patients with CHNM.
Uveal melanoma is the most frequent primary intraocular malignancy in adults and is characterized by an aggressive clinical course, high propensity for hepatic metastasis, and poor survival after metastatic progression. Improvements in ocular imaging and local therapies have improved primary tumor control, but approximately half of patients will ultimately develop metastatic disease with poor treatment options. Recent advances in genomics and molecular biology have dramatically improved our understanding of uveal melanoma pathogenesis, with the discovery of activating mutations in GNAQ , GNA11 , CYSLTR2 , and PLCB4 as early oncogenic events that drive aberrant signaling through the protein kinase C (PKC), MAPK, PI3K/AKT, and Hippo-YAP pathways. Additional changes in BAP1 , SF3B1 , and EIF1AX as well as common chromosomal aberrations, contribute to tumor progression, metastatic risk and clinical heterogeneity. New insights into the distinct immune landscape of uveal melanoma, including low tumor mutational burden, immune-desert and immune-excluded phenotypes, a macrophage-dominant microenvironment, and hepatic immune tolerance, have provided important explanations for its poor response to conventional immunotherapies. This review summarizes current knowledge on the epidemiology, risk factors, molecular pathogenesis, tumor microenvironment, diagnostic innovations and prognostic biomarkers of UM. We also review novel developments in molecular profiling, liquid biopsy, artificial intelligence-assisted diagnostics, and precision oncology strategies, as well as novel therapeutic approaches such as tebentafusp, protein kinase C inhibitors, immune checkpoint inhibitors, adoptive cell therapies, and liver-directed therapies. These advances are together changing the clinical management of uveal melanoma and provide new opportunities for personalized treatment, earlier detection of metastatic disease and improved patient outcomes.
Immune checkpoint inhibitor (ICI)-mediated dermatitis is a common treatment-related adverse event. We conducted single-nucleotide polymorphisms (SNPs)-array genotyping on germline DNA from 744 participants in a phase three adjuvant trial of ipilimumab in melanoma. Logistic regression was used to estimate associations between inherited genetic markers and the occurrence of dermatitis. We also tested previously reported dermatitis-related polygenic risk scores (PRS) adjusting for genetic ancestry. Dermatitis of any grade occurred in 52% (232 Gr1, 97 Gr2, and 52 Gr3). We identified two SNPs associated with dermatitis and subsequently developed a two-SNP PRS that was associated with dermatitis risk and severity. Both variants mapped to intronic regions of the insulin-like growth factor 1 receptor and A-kinase anchoring protein 12 genes, which have important roles in immune regulation and inflammatory response. Separately, 11 previously reported dermatitis-related PRSs derived from general population cohorts not exposed to immunotherapy were tested and none was associated with ICI-mediated dermatitis in our cohort. The cohort-derived PRS showed modest discrimination for dermatitis risk (AUC 0.63). The incidence of dermatitis was associated with improved outcomes; patients with grade 1-2 or any-grade dermatitis demonstrated improved relapse-free survival (RFS) (hazard ratio: 0.74; P = 0.007 and 0.77, P = 0.01, respectively). The cohort-derived PRS showed a trend toward improved RFS and overall survival. In conclusion, we generated a novel PRS associated with ICI-mediated dermatitis risk and severity that demonstrated a trend towards improved survival outcomes. Our findings support a role for inherited genetic variation in relation to ICI dermatitis and warrant further investigation.
Circulating tumor DNA (ctDNA) is an emerging noninvasive biomarker in melanoma, yet its clinical relevance varies by disease stage and tumor biology. This literature review integrates mechanistic concepts with clinical evidence to clarify where ctDNA provides meaningful insight for melanoma management. A comprehensive review of recent literature was conducted to evaluate biological mechanisms, detection methods, and clinical applications of ctDNA in melanoma care. Across multiple studies, detectable baseline ctDNA was consistently associated with worse overall and PFS, with hazard ratios generally ranging from 2 to 3. Low or undetectable pretreatment ctDNA correlated with improved outcomes in patients receiving immune checkpoint inhibitors and targeted therapies. Early ctDNA decline or clearance during treatment was associated with radiographic response, whereas persistent detectability suggested intrinsic resistance. Serial monitoring enabled identification of emerging resistance mutations, including NRAS, MEK1, and PI3K-pathway alterations, frequently preceding radiographic progression. In resected stage III melanoma, postoperative ctDNA positivity strongly predicted relapse, with hazard ratios approaching 10, and molecular recurrence often preceded clinical recurrence by several months. By contrast, early-stage melanoma demonstrated low ctDNA detection rates, often below 15%, reflecting limited tumor burden and low DNA shedding. Evidence is emerging to position ctDNA as a dynamic biomarker that complements conventional melanoma staging by capturing real-time tumor burden, treatment response, and residual disease. Its clinical utility is most robust in high-risk and advanced melanoma, where ctDNA reliably informs prognosis, molecular residual disease, and early relapse, while sensitivity constraints limit its current role in early-stage disease with low tumor burden.
Schisandrin C (Sch C), a lignan derived from Schisandra chinensis , exhibits antitumor activity in several malignancies; however, its effects on melanoma remain unclear. This study investigated the antitumor effects of Sch C on melanoma growth and metastasis and the underlying molecular mechanisms. Network pharmacology was used to predict potential targets of Sch C. In-vitro assays using B16-F10 melanoma cells evaluated proliferation, migration, invasion, apoptosis, and epithelial-mesenchymal transition (EMT). In-vivo antitumor activity was assessed in a murine melanoma xenograft model. Protein expression of key signaling molecules was analyzed by Western blotting and immunohistochemistry. Sch C significantly inhibited melanoma cell proliferation, migration, and invasion in a dose-dependent manner and promoted apoptosis. Sch C downregulated EMT-related proteins, including matrix metalloproteinase (MMP)-2, MMP-9, and vimentin, while upregulating E-cadherin. Mechanistically, Sch C reduced the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mechanistic target of rapamycin (mTOR) and was associated with modulation of Rap1-related signaling pathways. In vivo , Sch C markedly reduced tumor volume and weight without obvious toxicity and increased apoptosis while decreasing proliferation in tumor tissues. Sch C exerts antimelanoma effects and is associated with inhibition of PI3K/AKT/mTOR signaling and modulation of Rap1-related pathways, suggesting its potential as a therapeutic candidate for melanoma.
Primary care physicians typically perform the initial assessment of skin lesions. Artificial intelligence tools, using techniques such as convolutional neural networks, are under development and have shown promise for evaluating dermoscopic images for the detection of skin cancer. These tools could possibly support physicians. This study investigated possible factors that might affect the specificity of an artificial intelligence tool, associated with the patient, lesion, or dermoscopic characteristics, which clinicians could potentially avoid, or for which the tool could be optimized. A total of 228 dermoscopic images from a prospective clinical trial in primary care were retrospectively examined by a resident general practitioner using conventional dermoscopy algorithms to describe the lesion characteristics. All lesions falsely classified as melanomas suspected by the artificial intelligence tool in the trial were compared with the true negative lesions with regard to lesion and patient characteristics. Elevated lesions were more often correctly classified as benign compared with macular lesions [odds ratio (OR) = 16, 95% confidence interval (CI) = 2.0-120, P = 0.008]. The tool was more likely to falsely suspect melanoma if the ruler in the dermoscopic image was located over the lesion (OR = 2.0, 95% CI = 1.1-3.4, P = 0.017). This indicates that elevated lesions can be reliably assessed when using this type of tool, while the presence of a ruler might need attention in the optimization of artificial intelligence tools for melanoma assessment.
Stage IIB-IIC cutaneous melanomas carry a substantial risk of recurrence and disease-related mortality despite complete surgical excision, highlighting the need for reliable prognostic biomarkers. We retrospectively analyzed 153 patients with stage IIB-IIC cutaneous melanoma who underwent surgery at the Instituto Valenciano de Oncología between May 2000 and August 2024. Recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS) were estimated using Kaplan-Meier methods. Associations between clinicopathologic and molecular characteristics and survival outcomes were assessed by log-rank test and Cox proportional hazards models. At a median follow-up of 81.6 months, median RFS, DFS, and OS were 43, 31, and 50 months, respectively. In univariate analyses, both telomerase reverse transcriptase (TERT) promoter mutations [hazard ratio = 0.38, 95% confidence interval (CI) = 0.18-0.8, P = 0.008] and the absence of melanocortin-1 receptor (MC1R) variants (hazard ratio = 0.38, 95% CI = 0.16-0.91, P = 0.024) were significantly associated with RFS. In multivariate analyses, only TERT promoter mutations remained an independent predictor of both RFS (hazard ratio = 0.44, 95% CI = 0.20-0.96, P = 0.038) and DFS (hazard ratio = 0.47, 95% CI = 0.24-0.93, P = 0.030). Patients harboring TERT promoter mutations exhibited significantly poorer survival outcomes compared with those with wild-type TERT promoter status. Combined analysis supported the contrasting prognostic roles of TERT and MC1R. Our findings identify TERT promoter mutations as an independent prognostic factor and suggest a potential protective role of MC1R variants in stage IIB-IIC cutaneous melanoma.
Cutaneous melanoma incidence continues to rise worldwide, while advances in dermoscopic surveillance increasingly influence the stage at diagnosis. Long-term single-center analyses offer a unique perspective on how demographic shifts, tumor biology, and diagnostic intensity interact over time. We retrospectively analyzed 4062 consecutive patients with histologically confirmed cutaneous melanoma diagnosed between 2003 and 2024 at a tertiary dermatology center in Southern Italy. Demographic characteristics, anatomical site, and Breslow thickness were collected. Temporal trends were assessed using regression models and χ2 tests for trend. Melanoma diagnoses increased significantly over the study period ( P < 0.0001), with a near three-fold rise between the first (2003-2013) and second (2014-2024) decades. In parallel, the proportion of melanoma in situ increased from 38.2 to 57.5% ( P < 0.0001), indicating a pronounced shift toward earlier-stage detection. Mean age at diagnosis rose significantly over time ( P < 0.001). Trunk melanomas predominated overall, particularly among men, whereas lower limb melanomas were more frequent among women ( P < 0.001). Acral melanomas, although uncommon, showed the highest proportion of thick lesions (48.6%; ≥0.8 mm). Over two decades, melanoma diagnoses increased markedly alongside a substantial shift toward early stage disease. While these trends reflect improvements in surveillance and diagnostic sensitivity, the persistent burden of thick melanomas - particularly in acral locations and older patients - underscores unresolved diagnostic gaps.
In this prospective, survey-based study conducted from May 2023 to February 2025 at the Juravinski Cancer Center, patient preferences and perceptions of clinically meaningful outcomes in the adjuvant treatment of resected stage IIB-IV melanoma were evaluated. Sixty-four eligible patients with resected stage IIB-IV melanoma who were considering adjuvant systemic therapy completed an online survey assessing their understanding and prioritization of treatment outcomes, thresholds for meaningful clinical benefit, and willingness to accept toxicity risks. Overall survival (OS) and quality of life (QoL) emerged as the most important endpoints, prioritized by 37 and 31% of respondents respectively, with patients choosing surveillance tending to prioritize QoL while those on active treatment favoured OS. Willingness to accept disease-free/progression-free benefit in the absence of an OS benefit declined as the risk of potential side effects increased, even among patients who ultimately chose active treatment. Patients considered a reduction in recurrence risk from 27 to 10% over 2 years (stage IIB-IIC) and from 50 to 20% over 5 years (stage III-IV) to be clinically meaningful, accepting a median 10-12.5% risk of significant side effects, and desired a minimum cancer-free interval of 4.75 years. These findings suggest that while OS remained a primary concern, many melanoma patients placed high value on QoL and were cautious about initiating adjuvant therapies without demonstrable survival benefit. Reluctance to accept hypothetical treatment with potential toxicity contrasted with those who proceeded with treatment. This highlighted the importance of incorporating patient preferences and risk tolerance into shared decision-making and trial design.
Fully regressive melanoma is an exceedingly rare phenomenon characterized by the complete histopathologic disappearance of malignant melanocytes, replaced by fibrosis, melanophages, and lymphocytic infiltrates, without identifiable residual tumor cells. We report the case of a 71-year-old female who presented with a pigmented lesion of the right auricle, which was incidentally noted by her daughter. Clinical examination revealed a darkly pigmented, asymmetrical macule with retention of hair follicles, raising suspicion for a benign melanocytic nevus. Excisional biopsy revealed complete regression of a superficial spreading melanoma without measurable Breslow thickness or vertical growth phase. Immunohistochemical studies demonstrated positivity for melanocytic markers and a low proliferative index, while imaging with PET/computed tomography and MRI revealed no evidence of regional or distant metastasis. Given the absence of high-risk features, sentinel lymph node biopsy was not performed, and the patient underwent wide local excision with no residual malignancy identified. She remains disease-free under close clinical follow-up. This case highlights the diagnostic and management challenges associated with fully regressive melanoma and emphasizes the need for heightened clinical suspicion and individualized treatment strategies. Further research is required to better understand the prognostic significance and optimal follow-up protocols for this rare melanoma subtype.
Immune checkpoint inhibitors (ICIs), including programmed cell death-1 inhibitors such as nivolumab and cytotoxic T-lymphocyte-associated antigen-4 inhibitors such as ipilimumab, have become a cornerstone in the management of advanced melanoma, significantly improving survival outcomes. However, their use is increasingly associated with immune-related adverse events, including ocular inflammation. Although uncommon, ICI-associated uveitis represents a potentially sight-threatening complication with variable clinical presentation. We present a case of bilateral granulomatous panuveitis in a 56-year-old female receiving combined nivolumab and ipilimumab therapy for metastatic melanoma of unknown primary origin, together with a review of the literature. Ocular symptoms developed approximately 2.5 months after treatment initiation. Clinical examination revealed bilateral anterior chamber inflammation with granulomatous keratic precipitates, posterior synechiae, and vitritis accompanied by choroidal undulations. Infectious, systemic autoimmune etiologies and metastatic ocular involvement, were excluded. The clinical severity was consistent with the Common Terminology Criteria for Adverse Events grade 3 uveitis, necessitating systemic and pulsed corticosteroid therapy and discontinuation of immunotherapy. In melanoma patients receiving ICIs, uveitis most commonly presents as anterior uveitis but may also involve the posterior segment or manifest as panuveitis, including Vogt-Koyanagi-Harada-like phenotypes. Most cases occur within the first few months of treatment. Management is guided by disease severity, ranging from topical to systemic corticosteroids, with consideration of immunotherapy interruption. This case highlights the heterogeneous clinical spectrum of ICI-associated uveitis in melanoma and underscores the importance of early diagnosis and multidisciplinary management. Close collaboration between ophthalmologists and oncologists is essential to optimize both visual outcomes and melanoma treatment strategies.
Cutaneous melanoma is the most aggressive form of skin cancer, influenced by environmental and genetic factors, particularly immune-related genes like cytotoxic T-lymphocyte-associated protein 4 ( CTLA-4 ) and TNFRSF1B . We investigated the association of inherited single nucleotide variants in CTLA-4 (rs11571316, rs62182595, rs11571315, and rs4553808) and TNFRSF1B (rs3397, rs1061622, rs1061624, and rs1061628) with clinicopathological aspects and survival of 428 cutaneous melanoma patients. Carriers of CTLA-4 rs4553808 AG/GG plus TNFRSF1B rs3397 TC/CC genotypes were younger at diagnosis. The CTLA-4 rs4553808 AA plus TNFRSF1B rs1061624 GG genotypes were more common in male than female patients. CTLA-4 rs4553808 AA or rs62182595 GG plus TNFRSF1B rs1061624 GG were more frequent among patients with tumors on the head, neck, and trunk. Patients older than 54 years with CTLA-4 rs11571316 GG and TNFRSF1B rs3397 TT had a 3.04-times greater chance of progression to death because of tumor effects. Patients with head, neck, and trunk cutaneous melanoma carrying CTLA-4 rs4553808 AG/GG and TNFRSF1B rs1061624 GA/AA had a 2.30-times greater chance of recurrence, progression, or tumor-related death. Patients with head, neck, and trunk cutaneous melanoma carrying CTLA-4 rs4553808 AG/GG and TNFRSF1B rs1061624 GA/AA, and CTLA-4 rs62182595 GA/AA and TNFRSF1B rs1061624 GA/AA genotypes had a 2.97- and 2.75-times greater chance of progression to death because of tumor effects, respectively. These findings suggest immune modulation linked to these single nucleotide variants may facilitate cutaneous melanoma progression and highlight the potential for immunotherapeutic strategies in genetically predisposed patients.
Pregnancy-associated melanoma has long been debated, with hypotheses that gestational immune tolerance and elevated sex hormones may promote melanocytic transformation; however, large-scale, real-world evidence remains limited and conflicting. Using the TriNetX Global Collaborative Network, we conducted a retrospective cohort study of pregnant patients with documented first and third trimester encounters versus reproductive-age nonpregnant females with an encounter for contraceptive management and equivalent follow-up. Cohorts were 1:1 propensity-score matched on demographics, comorbidities relevant to immune function and cancer risk, and proxies for sun exposure and dermatologic surveillance. Incident invasive melanoma and melanoma in situ (MIS), stratified by anatomic site, were evaluated over a 21-month observation window corresponding to the duration of pregnancy plus 1 year postpartum. A sensitivity analysis restricted the pregnant cohort to patients with prior estrogen-based therapy exposure. In the primary analysis ( n = 854 193 per cohort), pregnancy was not associated with increased risk of invasive melanoma [hazard ratio: 0.92, 95% confidence interval (CI): 0.78-1.07) or MIS (hazard ratio: 1.01, 95% CI: 0.82-1.24), and no significant differences emerged at head and neck, trunk, or extremity subsites. In the sensitivity analysis ( n = 128 716 per cohort), findings were consistent, with no observed association with invasive melanoma (hazard ratio: 1.06, 95% CI: 0.76-1.49) or MIS (hazard ratio: 1.05, 95% CI: 0.67-1.65). Our results argue against pregnancy as an independent melanoma risk factor and point toward a baseline risk inherent to reproductive-age females.
Cutaneous melanoma is the most lethal form of skin cancer, accounting for a small fraction of global cancers but a disproportionate share of skin cancer deaths. Accurate detection of lymph node involvement is critical, as nodal metastasis reduces long-term survival in patients with melanoma. This study aimed to highlight the diagnostic accuracy of ultrasound in distinguishing cervical lymph nodes with melanoma metastasis from benign cervical lymph nodes. A retrospective review of 115 cervical lymph nodes from 87 patients who underwent fine needle aspiration biopsy for suspected melanoma metastasis was conducted. Sonographic images were independently assessed by two neuroradiologists for nodal margin, cortical echogenicity, hilum, vascular flow pattern, posterior acoustic enhancement, cystic change, calcification, and anteroposterior (AP) and transverse diameters. Of 115 nodes, 48 were metastatic, and 67 were benign. Cervical lymph nodes with melanoma metastasis more frequently exhibited irregular margins (P < 0.001), hypoechoic cortex (P = 0.02), obscured or absent hilum (P = 0.001), abnormal vascular flow (P < 0.001), posterior acoustic enhancement (P < 0.001), larger AP diameter (P < 0.001), and larger transverse diameter (P < 0.001) than benign nodes. Multivariate logistic regression incorporating age and sex into the model identified irregular margins [adjusted risk ratio (aRR) = 1.79, odds ratio (OR) = 7.63, P = 0.02], absent or disorganized vascular flow (aRR = 1.82, OR = 5.05, P = 0.01), and posterior acoustic enhancement (aRR = 1.90, OR = 6.61, P < 0.001) as independent predictors of malignancy.
