Search Results (53)

Introduction: Immune checkpoint inhibitors (ICIs) have transformed the treatment of metastatic melanoma; however, predictive markers of therapeutic response remain poorly defined. This study systematically assesses clinical, histological, and molecular predictors associated with survival outcomes in melanoma patients treated with ICIs. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, a systematic search was conducted in MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published between January 2018 and October 2025. Eligible studies reported associations between predictive factors and overall survival (OS) or progression-free survival (PFS) in adult melanoma patients receiving ICIs. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) from univariate (UVA) and multivariate analyses (MVA) were synthesized using random-effects meta-analyses. Results: Sex was not a consistent predictor (contradictory effects; PFS heterogeneity I² ≈ 90%), whereas older age predicted worse OS (MVA continuous: HR 1.05, 95% CI 1.02–1.08; UVA ≥ 65 vs. <65: HR 1.70, 95% CI 1.36–2.12). Poor performance status, assessed using the Eastern Cooperative Oncology Group (ECOG) scale, strongly predicted inferior outcomes (ECOG ≥ 1 vs. 0: MVA OS HR 2.01, 95% CI 1.61–2.51; MVA PFS HR 1.49, 95% CI 1.18–1.88; ECOG ≥ 2 vs. <2: MVA OS HR 2.24, 95% CI 1.79–2.81). Elevated lactate dehydrogenase (LDH) was consistently associated with poorer survival (MVA OS HR 1.71, 95% CI 1.53–1.91; MVA PFS HR 1.61, 95% CI 1.41–1.85), whereas body mass index (BMI) > 25 kg/m² was associated with improved OS (HR 0.82, 95% CI 0.68–0.98). Higher disease burden predicted worse prognosis (Stage IV vs. III: MVA OS HR 1.57, 95% CI 1.16–2.13; >2 metastatic sites vs. ≤2: MVA OS HR 2.38, 95% CI 1.40–4.07; brain metastases: MVA OS HR 1.69, 95% CI 1.30–2.20; MVA PFS HR 1.52, 95% CI 1.00–2.33). Histologic and molecular factors showed prognostic value: ulceration worsened OS (UVA HR 2.08, 95% CI 1.25–3.44) and PFS (UVA HR 2.97, 95% CI 1.39–6.32); acral subtype had poorer OS than cutaneous melanoma (MVA HR 2.99, 95% CI 1.63–5.48); high tumor mutational burden (TMB) improved PFS (UVA HR 0.47, 95% CI 0.33–0.70); and cutaneous immune-related adverse events (irAEs) were associated with favorable outcomes (skin disorders: UVA OS HR 0.26, 95% CI 0.14–0.47; UVA PFS HR 0.50, 95% CI 0.34–0.74). In contrast, detectable circulating tumor DNA (ctDNA) predicted markedly worse PFS (MVA HR 4.72, 95% CI 2.31–9.65) and a non-significant trend toward worse OS (MVA HR 3.34, 95% CI 0.96–11.67). Liver metastases and programmed death-ligand 1 (PD-L1) expression were not significantly associated with survival. Discussion: This meta-analysis synthesizes evidence on clinicopathologic, laboratory, and histopathologic predictors of immunotherapy outcomes in metastatic melanoma. Performance status, age, LDH, BMI, and metastatic burden consistently correlated with prognosis, while ulceration, disease stage, and TMB emerged as key histologic determinants. Conversely, PD-L1 and gender showed no consistent predictive value, whereas cutaneous immune-related adverse events and ctDNA reflected favorable and poor outcomes, respectively. These findings highlight the multifactorial nature of immunotherapy response and support the further development of integrated prognostic models to refine patient stratification and optimize treatment outcomes. Full article

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are pediatric inflammatory conditions with overlapping mucocutaneous features that may complicate early diagnosis. We performed a narrative review of the literature to characterize and compare cutaneous manifestations reported in children with KD and MIS-C and to assess their diagnostic relevance. Published studies describing dermatologic findings in patients aged 0–18 years were reviewed. The analysis revealed a broad heterogeneity of skin manifestations in both conditions, ranging from classic polymorphous rash and acral erythema to atypical presentations, including annular, psoriasiform, vesiculobullous, urticarial, and erythema nodosum-like lesions. Reactivation at Bacillus Calmette–Guérin vaccination sites and associated mucocutaneous findings, such as conjunctivitis and oral changes, emerged as supportive diagnostic clues, particularly for incomplete KD. Considerable overlap in cutaneous phenotypes between KD and MIS-C was observed, especially in patients with persistent fever and systemic inflammation, highlighting the risk of diagnostic delay. These findings underscore the importance of recognizing atypical dermatologic patterns as part of an integrated diagnostic approach, as delayed identification may increase the risk of cardiovascular complications. Early recognition of cutaneous clues can support timely initiation of immunomodulatory therapy and improve clinical outcomes. Full article

Background/Objectives: Acral melanoma (AM) is a rare and aggressive melanoma subtype that arises on sun-shielded, non-hair-bearing skin of the palms, soles, and nail beds. Although more common among individuals of non-European descent, AM remains underrecognized and understudied in the Middle East and North Africa (MENA). This study presents the first dedicated AM registry from Lebanon, aiming to characterize clinical, histopathological, and molecular features and evaluate diagnostic, referral, treatment approaches, and clinical outcomes over a 12-year period. Methods: This retrospective cohort study was conducted at the American University of Beirut Medical Center (AUBMC), a major tertiary referral center in the MENA region. All melanoma cases diagnosed between January 2012 and January 2024 were identified through electronic health records. From this cohort, all adult patients (≥18 years) with biopsy-confirmed AM or tumors located on the palms, soles, or under the nails were selected. Results: Our cohort consisted of 26 adult AM patients, identified from a total of 331 melanoma cases during the study period (8%). Median age at diagnosis was 58.5 years; 54% were female; and 96% of Middle Eastern origin. Most tumors were plantar (81%), and over half (53%) were diagnosed at early stages (Stage I–II). Surgery was performed in 92% of patients, yet 55% had positive margins. Sentinel lymph node biopsy was performed in 46%, and 35% received immunotherapy. Only 35% underwent molecular testing, identifying BRAF mutations in 11% of those tested; no patients received circulating tumor DNA analysis. At a median follow-up of 24.5 months, recurrence occurred in 27%, and metastasis developed in 23%. At the last follow-up, 92% were alive. Conclusions: Despite early-stage detection, high rates of positive margins and limited molecular testing reveal care gaps. This first national registry highlights the need to improve surgical management and expand access to precision oncology in the region. Full article

Melanoma is an aggressive form of skin cancer marked by unique genetic alterations that promote tumor growth and resistance to therapy. Advances in targeted therapy have markedly improved clinical outcomes by selectively inhibiting key oncogenic pathways. This review focuses on three clinically relevant agents—vemurafenib, trametinib, and imatinib—analyzing their mechanisms of action, clinical applications, efficacy, and limitations. Vemurafenib, a selective BRAFV600E inhibitor, significantly extends progression-free and overall survival in BRAF-mutant melanoma but is limited by acquired resistance and frequent cutaneous toxicities. Trametinib, a MEK1/2 inhibitor, acts downstream in the MAPK pathway and is typically combined with BRAF inhibitors to enhance efficacy and delay resistance. Imatinib, targeting c-KIT and PDGFR mutations, demonstrates therapeutic benefit primarily in acral and mucosal melanoma subtypes, though with lower response rates than BRAF-directed therapies. Adverse events associated with these drugs are generally manageable with appropriate monitoring. Despite substantial advances, secondary mutations and reactivation of oncogenic signaling remain major challenges. This narrative review integrates data from clinical, preclinical, and real-world studies to update the current understanding of targeted therapies in cutaneous melanoma and highlight ongoing research aimed at overcoming resistance and optimizing personalized treatment strategies. Full article

Background: PLACK syndrome is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in CAST, which encodes calpastatin, an endogenous inhibitor of calpains. The syndrome is classically defined by peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads. Although the phenotype has been largely restricted to dermatological manifestations, emerging reports suggest dilated cardiomyopathy (DCM) as a systemic complication. Methods: We investigated five affected children from three sibships of an extended consanguineous family. Clinical evaluation and genome sequencing (GS) followed by segregation analysis of the targeted mutation test (TMT) were performed. Histopathological examination of an explanted heart was conducted in one child who underwent heart transplantation. Results: All affected children exhibited typical dermatological features of PLACK syndrome. Four developed severe DCM, two of whom required orthotopic heart transplantation. GS, performed in three affected children, identified a novel homozygous frameshift variant in CAST (NM_001750.7:c.1177dup, p.Arg393Profs*4), which segregated with the disease within the family. No additional plausible variants in known cardiomyopathy-associated genes were detected. Histopathological examination of the explanted heart demonstrated hypertrophied cardiomyocytes with nuclear enlargement, hyperchromasia, and fibrosis. Conclusions: Our findings expand the phenotypic spectrum of PLACK syndrome to include severe DCM and suggest CAST deficiency as a novel cause of recessively inherited cardiomyopathy. The favorable short-term outcome following transplantation highlights a potential therapeutic option. Given the possibility of age-dependent penetrance, lifelong cardiac surveillance is for the affected individuals suggested. To emphasize cardiomyopathy as a critical and underrecognized component of the syndrome, we propose the consideration of modifying the acronym to PLACK-C. Full article

Melanoma shows heterogeneity across body sites like skin, acral skin, and the uvea, driven by molecular characteristics and genetic variations. However, comparative studies exploring the heterogeneity of melanoma across different anatomical sites remain limited, hindering a comprehensive understanding of its underlying biology. We proposed a research framework through bioinformatics to analyze the tumor ecosystems of cutaneous, acral, and uveal melanoma, from molecular characteristics to genetic variations at single-cell resolution. We found that oxidative phosphorylation (OXPHOS) is a critical driver of tumor cell evolution, with abnormal ribosomal gene and tumor suppressor expression observed in uveal melanoma (UM). Additionally, we screened for potential drug targets and drugs against tumor cells. In the immune microenvironment, acral melanoma (AM) and UM exhibit stronger immunosuppressive characteristics compared to cutaneous melanoma (CM). OXPHOS contributes to T cell cytotoxicity dysregulation in CM and AM, while interferon-γ is crucial in UM. Tumor cells may also induce T cell dysfunction through biological signals such as MIF-CD74 and HLA-E-NKG2A. This study offers valuable insights into melanoma heterogeneity, providing a comprehensive research framework for understanding the distinct molecular and immune characteristics of CM, AM, and UM, and potentially guiding the development of therapeutic strategies tailored to each melanoma subtype. Full article

Background: Melanoma is one of the most aggressive types of skin cancer. Its diagnosis appears to be challenging due to morphological similarities to benign melanocytic lesions. Even though histopathological evaluation is the diagnostic gold standard, immunohistochemistry (IHC) proves to be useful in challenging cases. Preferentially Expressed Antigen in Melanoma (PRAME) has emerged as a promising diagnostic, prognostic, and therapeutic marker in melanoma. Methods: This review critically examines the role of PRAME across clinical domains. It presents an evaluation of PRAME’s diagnostic utility in differentiating melanomas from benign nevi, its prognostic significance across melanoma subtypes, and therapeutic applications in emerging immunotherapy strategies. An extensive analysis of the current literature was conducted, with a focus on PRAME expression patterns in melanocytic lesions and various malignancies, along with its integration into IHC protocols and investigational therapies. Results: PRAME demonstrates high specificity and sensitivity in distinguishing melanoma from benign melanocytic proliferations, particularly in challenging subtypes such as acral, mucosal, and spitzoid lesions. Its overexpression correlates with poor prognosis in numerous malignancies. Therapeutically, PRAME’s HLA class I presentation enables T-cell-based targeting. Early-phase trials show promising results using PRAME-directed TCR therapies and bispecific ImmTAC agents. However, immune evasion mechanisms (i.e., heterogeneous antigen expression, immune suppression in the tumor microenvironment, and HLA downregulation) pose significant challenges to therapy. Conclusions: PRAME is a valuable biomarker for melanoma diagnosis and a promising target for immunotherapy. Its selective expression in malignancies supports its clinical utility in diagnostic precision, prognostic assessment, and precision oncology. Ongoing research aimed at overcoming immunological barriers will be essential for optimizing PRAME-directed therapies and establishing their place in the personalized management of melanoma. Full article

Background and Clinical Significance: Angioleiomyoma (ALM) is a benign tumor that generally presents as a single lesion and, according to the updated WHO classification, includes the following three histological subtypes: solid (or capillary), cavernous, and venous. Typically, ALMs are described as well-defined nodules in the lower extremities but are unusually located in the acral locations and toes. We summarize two cases of ALM and perform a systematic review to provide foot surgeons with the most up-to-date and useful information on the epidemiological aspects, anatomical distribution, and specific histological subtypes of ALM in the foot. Materials and Methods: A systematic review was carried out according to the criteria of a PICO framework, and a systematic search and data processing were carried out according to the PRISMA guidelines. We analyzed patient demographics, clinical characteristics, diagnostic workup, treatment, and clinical outcomes. Each one of the included articles was independently assessed for methodological quality and risk of bias by an independent evaluator. The risk of bias of the included studies was assessed based on their characteristics. Results: This systematic review included 14 case series with 172 reported cases of ALM. One hundred and seventy-two (18.57%) were cases of ALM located on foot, excluding the ankle region. The female-to-male ratio was 1.48. The most common location was the hindfoot (41.5%), followed by the forefoot (20.2%) and the midfoot (8.9%). In 29.4% of cases, the location of the lesions could not be determined. The most frequent location of the lesions was subcutaneous (69%), followed by subaponeurotic (16.5%) and skin (14.5%) locations. The most frequent histological presentation was the solid histologic subtype (65%), followed by the venous subtype (21%) and the cavernous subtype (14%), respectively. Of the total reported cases of ALM located in foot, 63.1% presented as solid painful lesions. Calcified presentations occurred in 7% of cases, with more than half of the cases located in the hindfoot. Surgical excision was the treatment of choice in the two herein reported cases of solid ALM located in the hindfoot, one of them with a calcified presentation. No recurrence was observed in either case after two and five years of follow-up, respectively. All cases reviewed after surgical excision showed a low recurrence rate with a favorable prognosis regardless of the histological subtype and a very rare tendency toward malignancy. Conclusions: ALMs of the foot present as well-defined, painful nodules in the subcutaneous tissue of middle-aged women. Solid histological subtypes are the most prevalent. Histopathological analysis is usually essential for confirmation. Treatment consists primarily of direct excision, with remarkably low recurrence rates. Full article

Cutaneous manifestations can serve as early and sometimes the first clinical indicators in various hereditary cancer predisposition syndromes. This review provides a comprehensive overview of the dermatological signs associated with these syndromes, aiming to facilitate their recognition in clinical practice. Hereditary Breast and Ovarian Cancer syndrome is notably linked to an increased risk of melanoma. BAP1 tumor predisposition syndrome is characterized by BAP1-inactivated melanocytic tumors. Muir–Torre syndrome, a variant of Lynch syndrome, presents with distinctive cutaneous neoplasms such as sebaceous carcinomas, sebaceous adenomas, and keratoacanthomas. PTEN hamartoma tumor syndrome commonly features hamartomatous growths, trichilemmomas, acral keratoses, oral papillomas, and genital lentiginosis. Gorlin syndrome is marked by basal cell carcinomas and palmoplantar pits, while Peutz–Jeghers syndrome is identified by mucocutaneous pigmentation. In familial adenomatous polyposis, the cutaneous findings include epidermoid cysts, fibromas, desmoid tumors, and lipomas. Additionally, we examined monogenic disorders associated with cancer risk and skin involvement, such as xeroderma pigmentosum, neurofibromatosis type 1, familial atypical multiple-mole melanoma syndrome, and Fanconi anemia. The early recognition of these dermatologic features is essential for a timely diagnosis and the implementation of appropriate surveillance strategies in individuals with hereditary cancer syndromes. Full article

Background/Objectives: Cowden syndrome (or PTEN hamartoma tumor syndrome) (CS/PHTS) belongs to a group of inherited disorders associated with the development of multiple hamartomas. The clinical presentation of patients may include dysmorphic facial features, macrocephaly, developmental delay, and multiple benign and malignant tumors of various localizations. At the same time, only thyroid cancer is thought to have an increased risk in childhood. Skin lesions in CS/PHTS occur in 90–100% of patients and include multiple tricholemmoma, papilloma, acral keratosis, pigmentation changes, as well as rarer forms like vascular malformations, fibromas, neuromas, melanoma, and basal cell carcinoma. Methods: Next-generation sequencing and Sanger sequencing were used to search for PTEN genetic variants. A histological and immunohistochemical examination of tumor biopsies and skin lesions was performed. Results: A total of 13 patients from six families with CS/PHTS, including 10 children, were described. Seven pediatric patients belonged to families with paternal transmission of the PTEN pathogenic variants, while three others were de novo cases. Atypical manifestations in CS/PHTS were diffuse large B-cell lymphoma in one adult, a renal cell carcinoma, three germ cell tumors, and a linear epidermal nevus in pediatric patients. A literature review of the identified pathogenic variants in the PTEN gene was performed, assessing their clinical significance and analyzing the traditional and modified diagnostic criteria as applied to the pediatric population. Conclusions: Taking into account the low incidence of CS/PHTS, the data presented significantly expand our current understanding of this disease and guide physicians to consider a wider range of possible malignant neoplasms in pediatric patients with CS/PHTS. Full article

Background: Melanoma, a highly aggressive form of skin cancer, necessitates early detection to significantly improve survival rates. Traditional diagnostic techniques, such as white-light imaging (WLI), are effective but often struggle to differentiate between melanoma subtypes in their early stages. Methods: The emergence of the Spectrum-Aided Vison Enhancer (SAVE) offers a promising alternative by utilizing specific wavelength bands to enhance visual contrast in melanoma lesions. This technique facilitates greater differentiation between malignant and benign tissues, particularly in challenging cases. In this study, the efficacy of the SAVE is evaluated in detecting melanoma subtypes including acral lentiginous melanoma (ALM), melanoma in situ (MIS), nodular melanoma (NM), and superficial spreading melanoma (SSM) compared to WLI. Results: The findings demonstrated that the SAVE consistently outperforms WLI across various key metrics, including precision, recall, F1-scorw, and mAP, making it a more reliable tool for early melanoma detection using the four different machine learning methods YOLOv10, Faster RCNN, Scaled YOLOv4, and YOLOv7. Conclusions: The ability of the SAVE to capture subtle spectral differences offers clinicians a new avenue for improving diagnostic accuracy and patient outcomes. Full article

Background/Objectives: Genetics and epigenetics play an important role in the pathogenesis of cutaneous melanoma. The majority of cases harbor mutations in genes associated with the MAPK signaling pathway, i.e., BRAF, NRAS, or NF1. The remaining neoplasms, often located on acral sites, are condensed as the triple-wildtype subtype and are characterized by other molecular drivers. This study aimed to elucidate genetic and epigenetic differences within cutaneous melanoma and to compare it with melanocytic nevi. Methods: DNA was extracted from archived tissue samples of cutaneous melanoma (n = 19), melanocytic nevi (n = 11), and skin controls (n = 11) and subsequently analyzed by massive parallel (next generation) gene panel sequencing and genome-wide DNA methylation array analysis. The sample size was increased by including repository data from an external study. Results: There were major differences in the genomic landscape of MAPK-altered and triple-wildtype cutaneous melanoma, the latter presenting with a lower number of mutations, a different pattern of copy number variants, and a low frequency of TERT promoter mutations. Dimensional reduction of DNA methylation array analysis clearly separated cutaneous melanoma from melanocytic nevi but revealed no major differences between classical cutaneous melanoma and the triple-wildtype cases. However, it identified a possible biological subgroup characterized by intermediately methylated CpGs. Conclusions: Dimensional reduction of methylation array data is a useful tool for the analysis of melanocytic tumors to differentiate between malignant and benign lesions and may be able to identify biologically distinct subtypes of cutaneous melanoma. Full article

Introduction: Acral lentiginous melanoma (ALM), a rare subtype, accounts for 2–3% of melanoma cases, primarily affecting the palms, soles, and nail beds and disproportionately affects people of color. This review focuses on clinical insights into ALM and its management, with a focus on race and ethnicity. Methods: A comprehensive literature search was conducted in public databases using the search term “acral melanoma,” and studies focusing on epidemiology, clinical presentation, and treatment outcomes of ALM in various racial and ethnic groups were reviewed. Results: Significant disparities in ALM outcomes exist across racial and ethnic groups, with African, Hispanic, and Asian individuals presenting with thicker, more advanced tumors at diagnosis. These populations encounter unique challenges, including limited access to dermatologic care, under-recognition of melanoma presentation in darker skin types, and socioeconomic barriers leading to delayed diagnosis and treatment. Surgical management may require specialized approaches, such as partial amputation for subungual melanomas. Additionally, there is uncertainty regarding the tumor immune microenvironment (TME) in ALM, with some studies suggesting that it might be less favorable, resulting in a lower response to immunotherapy. Conclusions: ALM affects diverse populations, and the impact of ethnic and racial origin on ALM biology is largely unknown. Addressing disparities in ALM outcomes among racial and ethnic groups is critical for improving patient care. Increased awareness of melanoma risk in individuals with darker skin can significantly impact early detection and treatment. Future research should focus on the genetic and biological factors contributing to morbidity and mortality in ALM patients. Full article

Acral melanoma is a distinct subtype of cutaneous malignant melanoma that uniquely occurs on ultraviolet (UV)-shielded, glabrous skin of the palms, soles, and nail beds. While acral melanoma only accounts for 2–3% of all melanomas, it represents the most common subtype among darker-skinned, non-Caucasian individuals. Unlike other cutaneous melanomas, acral melanoma does not arise from UV radiation exposure and is accordingly associated with a relatively low tumor mutational burden. Recent advances in genomic, transcriptomic, and epigenomic sequencing have revealed genetic alterations unique to acral melanoma, including novel driver genes, high copy number variations, and complex chromosomal rearrangements. This review synthesizes the current knowledge on the clinical features, epidemiology, and treatment approaches for acral melanoma, with a focus on the genetic pathogenesis that gives rise to its unique tumor landscape. These findings highlight a need to deepen our genetic and molecular understanding to better target this challenging subtype of melanoma. Full article