Search Results (192)

Head and neck mucosal melanoma (HNMM) arises in the nasal and oral cavities and has the propensity to metastasize to local and distant body sites. HNMM is also notable for its resistance to available therapeutics. The rarity of this disease makes it difficult to conduct large-scale clinical studies to develop standard treatment protocols. In contrast to cutaneous melanoma, c-Kit-dependent pathways are well studied in HNNMM and provide a potential therapeutic target. We identified and isolated genetically distinct subpopulations with stem cell characteristics in HNMM samples bearing Kit wild-type and mutations. Functional analysis of these subpopulations reveals that, in addition to expressing the stem cell marker proteins CD20, CD117, CD133, and CD166, these subpopulations are characterized by self-renewal potential, migratory capacity, and resistance to Kit inhibitors such as Imatinib. Immunofluorescence staining and inhibition experiments demonstrate that the maintenance and resistance of HHMM subpopulations to Kit inhibitors is mediated by the Kit signal to the PI3K signaling pathway. The KIT signal to the PI3K signaling pathway does not result exclusively from a KIT mutation localized to Exon 17, but can also be triggered by mutations localized to Exons 11 and 13. In the present study, we identify and characterize an HNMM subpopulation with stemness properties in patients with c-Kit wild-type and mutation, and demonstrate for the first time the mechanisms by which the CD117⁺/CD133⁺ HNMM subpopulations survive and confer resistance to the specific inhibitor of c-Kit mutation. Full article

Background and Objectives: Cutaneous squamous cell carcinoma (cSCC) displays heterogeneous metastatic potential, and the role of sentinel lymph node biopsy (SLNB) in clinically node-negative patients remains debated. To evaluate tumor thickness and histological grade as predictors of sentinel lymph node (SLN) metastasis in high-risk cSCC and to assess the performance of a simplified pathology-based predictive model. Materials and Methods: This retrospective single-center study included consecutive patients with high-risk cSCC and clinically N0 status who underwent SLNB. Associations were examined using univariate and multivariable logistic regression, ROC analysis with bootstrap internal validation (2000 iterations), and decision curve analysis. Results: Thirty-four patients were analyzed; 12 (35.3%) had SLN metastases. SLN-positive patients had greater tumor thickness (median 5.5 mm vs. 3.0 mm, p = 0.006) and higher frequency of G2–G3 histological grade (91.7% vs. 45.5%, p = 0.011). Histological grade was the strongest independent predictor in multivariable analysis (OR 14.61, 95% CI 1.63–131.12). The combined model demonstrated apparently high discrimination in this small cohort (AUC 0.91; bootstrap 95% CI 0.79–0.99), though this estimate should be interpreted with caution given the limited number of events. A 4.0-mm threshold yielded sensitivity 83.3% and NPV 86.7%. Conclusions: In this exploratory single-center study, tumor thickness and histological grade were complementary predictors of SLN metastasis in cSCC. These findings are preliminary and require validation in larger prospective cohorts. Full article

Background/Objectives: Phyllodes tumors are rare fibroepithelial neoplasms of the breast, accounting for less than 1% of all breast tumors and approximately 2–3% of breast fibroepithelial tumors. They can be benign, borderline, or malignant, depending on cellular atypia and stromal invasion. Although most display local behavior, malignant forms can metastasize hematogenously, most frequently to the lungs, bones, and liver, with lymph node metastases being exceptional. Case Presentation: We analyzed the case of a 47-year-old woman with a phyllodes breast tumor weighing approximately 5 kg. The tumor evolved slowly over five years, followed by accelerated growth, cutaneous necrosis, superinfection, and severe anemia. Total mastectomy was performed, and histopathological examination confirmed the diagnosis of a malignant phyllodes tumor. Five months after surgery and adjuvant radiotherapy, the patient developed laterocervical metastases with thyroid invasion and life-threatening tracheal compression, an extremely rare presentation for this type of tumor in adults. Discussion/Conclusions: This case illustrates the aggressive and unpredictable behavior of malignant phyllodes tumors and underscores the necessity of careful oncological monitoring and a multidisciplinary approach, given their potential for dissemination to unusual locations. Full article

Invasive conjunctival squamous cell carcinoma (CSCC) is an aggressive, ocular surface malignancy. The mean annual age-standardised incidence rate of 0.45 cases per million per year is increasing with an average annual percent rise of 4.5% and occurs mainly in over 65-year-olds in temperate climates but in a younger demographic in the tropics. Invasive CSCC can lead to vision loss either from the destructive effects of the tumour or side effects of therapy, facial disfigurement from radical surgery, and death from metastases. There is no standardised treatment and not all cases are referred to a specialist ocular oncology centre. Recent progress in cancer immunology and genetics has revolutionised the treatment of cutaneous and head and neck SCCs, which share some similarities to invasive CSCC. A better understanding of invasive CSCC and its preinvasive intraepithelial lesions is required to lead to the development of novel targeted and immunotherapies both for local tumour control, globe sparing alternatives and to prevent disseminated disease. This review aims to provide a comprehensive clinical overview of the current knowledge regarding CSSC, its epidemiology, pathogenesis, presentation, diagnosis, management, recent advances in targeted and immunotherapies for personalised treatment of this disease, and early diagnosis strategies to improve patient outcomes. Full article

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

Prostate cancer is the most common non-cutaneous malignancy in men and is the second leading cause of male cancer-related mortality. Unlike many cancers, prostate cancer lacks clear genetic driver mutations, suggesting that factors in the tumor microenvironment contribute to the genesis and progression of this disease. Hypoxia, or a physiological state of low oxygen, is a universal characteristic of solid tumors that enhances disease progression and therapeutic resistance. Prostate cancer develops in a hypoxic microenvironment and primarily metastasizes to bone, where oxygen availability is similarly limited. Therefore, hypoxia is a major obstacle to the effective treatment of prostate cancer across all disease stages. Clinically, hypoxia is correlated with worse patient outcomes, largely because it drives resistance to the frontline therapies used to treat both primary and metastatic prostate cancer. Despite the established role of hypoxia in prostate cancer progression and drug resistance, it has not been successfully targeted therapeutically. Emerging evidence indicates that exposure to distinct temporal patterns of hypoxia (acute, cyclic, and chronic) elicits unique cellular adaptations that dictate tumor growth and survival. This review synthesizes current evidence regarding the role of hypoxia in promoting resistance to therapy in prostate cancer. Full article

Cutaneous metastases are an uncommon but clinically relevant manifestation of breast cancer (BC), often indicating advanced disease and biological progression. Temporal heterogeneity between primary tumors and metastatic lesions, particularly involving hormone receptors (HRs) and HER2 status, may influence prognosis and treatment decisions. We retrospectively analyzed BC patients with cutaneous metastases diagnosed at a tertiary care center between 2015 and 2024. Clinical data, histopathological features, and immunohistochemical profiles of estrogen receptor (ER), progesterone receptor (PgR), and HER2 were evaluated in paired primary tumors and cutaneous metastatic lesions under uniform pre-analytic and analytic conditions. Receptor discordance and survival outcomes were assessed. Among 660 patients with metastatic BC, 28 (4.2%) developed cutaneous metastases. Median age at diagnosis was 63 years, with chest wall as the most frequent site of skin involvement. HR-positive/HER2-negative tumors were predominant, while triple-negative breast cancer accounted for 19.4% of cases and was associated with a shorter disease course and earlier cutaneous metastatic spread. Receptor discordance occurred in 18.2% for ER, 36.4% for PgR and 41.4% for HER2, mainly involving transitions to or from HER2-low status. After skin involvement, prognosis remained poor. Cutaneous BC metastases show marked receptor heterogeneity, reflecting dynamic tumor evolution. These findings support re-biopsy and biomarker reassessment to guide personalized treatment in metastatic BC. Full article

Background: Cutaneous melanoma metastases (CMM) represent a clinically relevant manifestation of advanced melanoma and may constitute the first sign of disseminated disease. Their diagnosis is challenging because CMM shows highly variable clinical and dermoscopic presentations and frequently mimic other benign or malignant skin lesions. Although dermoscopy is routinely used to improve skin lesion assessment, dermoscopic criteria specific to CMM remain poorly defined and still non-standardized. Methods: We performed a narrative review of the literature to summarize dermoscopic features reported in CMM. MedLine (via PubMed) and Web of Science were searched up to 3 December 2025 using the keywords “dermoscopy” and “melanoma metastasis,” complemented by manual reference screening. Eligible studies were English-language full-text articles in peer-reviewed journals providing a complete dermoscopic description. Extracted data included patient demographics and major dermoscopic criteria, categorized as global patterns and focal dermoscopic and vascular structures. Due to heterogeneity, results were synthesized descriptively. Results: Twenty studies were included, comprising 774 patients. Dermoscopic findings were markedly heterogeneous. Globally, lesions frequently showed homogeneous pigmentation with variable colors and included amelanotic presentations. Commonly evaluated focal features included irregular dots and globules, crystalline structures, peripheral gray dots, and lacuna-like areas. Vascular patterns were prominent, particularly serpentine and corkscrew-like vessels. Conclusions: CMM dermoscopy is characterized by substantial heterogeneity and a lack of standardized criteria. Systematic classification of recurring dermoscopic features may improve diagnostic consistency and provide an interpretable framework for future artificial intelligence-based approaches supporting non-invasive recognition of melanoma metastases. Full article

Background: Cardiac metastases from cutaneous melanoma are uncommon and often underdiagnosed due to their variable and frequently asymptomatic presentation. To better describe their clinical features, diagnostic strategies, and outcomes, we performed a systematic review of published case reports and present an illustrative clinical case. Case presentation: We report the case of a 67-year-old man with a history of stage IIA cutaneous melanoma who presented with progressive fatigue and dyspnea. Disease recurrence was confirmed by skin biopsy. Multimodal imaging, including echocardiography, FDG PET-CT, and cardiac magnetic resonance (CMR), demonstrated extensive myocardial infiltration consistent with cardiac metastases. Despite treatment with immunotherapy, the patient experienced progressive clinical deterioration and died six months after diagnosis. Discussion: The systematic review encompassed 23 published articles reporting 27 individual cases, with a mean age at diagnosis of 55.9 years and a clear male predominance. Cardiac involvement exhibited marked heterogeneity in both clinical presentation and anatomical distribution, most frequently affecting the left ventricular free wall and the interventricular septum. Echocardiography consistently served as the initial diagnostic modality, while cardiac magnetic resonance and CT/FDG PET-CT were used to refine lesion characterization and assess extracardiac disease. Notably, a complete multimodal imaging strategy was reported in fewer than one-third of cases, reflecting variability in diagnostic approaches. Survival outcomes were highly heterogeneous, with substantial mortality, underscoring the need for earlier detection and more accurate diagnostic strategies for cardiac involvement in melanoma. Conclusions: Cardiac metastases from melanoma represent advanced disease and remain associated with poor and heterogeneous outcomes. An integrated multimodal imaging approach supports detailed diagnostic characterization and may aid clinical evaluation and management in selected cases. Full article

Background/Objectives: Cutaneous metastases from primary bone sarcomas are exceedingly rare and poorly characterized, often posing diagnostic challenges due to their atypical presentation. This systematic review aimed to describe the clinical patterns, temporal relationships, and prognostic implications of cutaneous metastases across major bone sarcoma histologies. Methods: A comprehensive literature search was conducted to identify all reported cases of cutaneous metastases from osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma. Data on patient demographics, primary tumor site, cutaneous lesion characteristics, latency periods, synchronous metastases, morphology, and clinical outcome were extracted and analyzed descriptively. Results: 102 cases were identified, with chordoma representing the most frequent histology. Cutaneous metastases showed histology-specific patterns: osteosarcoma and Ewing sarcoma typically presented with multiple lesions in the context of widespread systemic disease and poor prognosis, whereas chordoma more often exhibited solitary or skin-dominant metastases with longer latency and occasional favorable outcomes, including complete responses after local treatment. Conclusions: Cutaneous metastases in bone sarcomas display heterogeneous behavior, with chordoma demonstrating a more indolent and potentially manageable pattern compared to other histologies. Increased clinical awareness is essential to avoid diagnostic delays and optimize management. Full article

Background/Objectives: Uveal melanoma (UM) is a subtype of melanoma that originates from the uveal layer of the eye (iris, ciliary body, choroid) and is biologically distinct from cutaneous melanoma. The real-world evidence on treatment patterns and survival outcomes, particularly from non-Western populations, remains limited. This study provides a comprehensive national overview of local and systemic management of UM across Türkiye. Methods: This multicenter retrospective cohort study, coordinated by the Turkish Oncology Group (TOG), included patients diagnosed with UM between 2012 and 2025 across 19 tertiary oncology centers. Clinical characteristics, treatment patterns, and outcomes were analyzed. Systemic therapies were subgrouped as immunotherapy or cytotoxic chemotherapy. Progression-free survival (PFS) and overall survival (OS) were assessed by the Kaplan–Meier method; prognostic factors for OS were analyzed by Cox regression. Results: A total of 113 patients were included; 89.4% presented with localized disease. During follow-up, 43.4% developed metastases, predominantly hepatic (93.5%). 47.4% of metastatic patients received liver-directed treatments; the most common treatment was radioembolization, and these treatments were associated with longer OS. Among 59 patients receiving systemic therapy, immunotherapy demonstrated higher ORR and DCR than chemotherapy across treatment lines, although small subgroup sizes limited statistical significance. Dual immune checkpoint blockade emerged as an independent favorable prognostic factor in multivariate analysis. Median OS for metastatic patients was 16 months (95% CI: 9.3–22.7). HLA-A*02:01 was positive in 29.4% of patients tested, and only three patients received tebentafusp. Conclusions: This large national cohort highlights substantial real-world heterogeneity in treatment patterns and confirms the limited efficacy of chemotherapy, the prognostic benefit of dual ICI therapy, and the potential survival advantage of liver-directed treatments in selected patients. Low HLA-A*02:01 positivity and limited access to tebentafusp remain major challenges in Türkiye. These findings provide an essential benchmark for improving treatment strategies in metastatic UM. Full article

Background: Cutaneous squamous cell carcinoma (CSCC) is the second most common neoplasm in humans and the most frequent in Brazil (80% in the head and neck region, 20% mortality). Brazil is a world leader in organ transplants (more than 30,000 transplants in 2019). The risk of transplant patients (Tx) developing CSCC is 65–250 times higher, with deeper infiltration, advanced stage, higher local recurrence, occult metastases, and worse survival. Objective: To investigate the prognostic factors of locally advanced cutaneous squamous cell carcinoma (LACSCC) of the head and neck region in transplant patients. Methods: 16-year retrospective, single-center series of patients with LACSCC in the head and neck region who underwent surgical treatment. Clinical and Tx data, clinical/pathological stage, surgical treatment, parotid/regional and distant metastases, recurrence, and survival were analyzed. Results: 156 patients were included: 69.2% women, 65.3 years; mean primary size: 4.24 cm, 66% T3/T4 tumors, 71% grade 2/3 differentiation, 20.5% transplant recipients, follow-up: 33.6 months. The most affected regions were malar/nasal (28.8%) and auricular (19.2%). Surgeries included wide resection with reconstruction (58.9%), exenteration (14.1%), and temporalectomy (11.5%). Univariate analysis: Recurrence: immunosuppressor drugs (p = 0.009), transplanted (p = 0.006), compromised margin (p = 0.049); Mortality: immunosuppression (p = 0.028), total resection and reconstruction (p = 0.013), stage (8ed) III-IV (p < 0.001), compromised margin (p < 0.001), neck metastasis with extranodal extension (p = 0.018). Multivariate analysis: Recurrence: transplanted HR: 3.69 (p < 0.001), neck metastasis extranodal extension HR: 5.41 (p < 0.001), evolution to distant metastasis HR: 5.27 (p < 0.001); Mortality: neck metastasis extranodal extension HR: 1.94, (p = 0.032), compromised margins HR: 1.87 (p = 0.001). Main surgical procedures: temporalectomy HR: 2.83 (p = 0.007), major rhinectomy HR: 2.47 (p = 0.005); Worst overall survival: Tx compared to NonTx (p = 0.069); Worst survival with recurrence: Tx compared to NonTx (p = 0.005). Conclusions: The LACSCC and transplanted (immunosuppressed) group present low survival, worse prognosis; The formulation of specific guidelines to standardize treatment and predict outcomes on this population are strictly necessary. Full article

Background and Clinical Significance: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cutaneous malignancy with increasing incidence among elderly, immunocompromised patients or individuals exposed to ultraviolet radiation. Case Presentation: We present the case of an 84-year-old Caucasian male with no history of immunosuppression, who was admitted for asthenia, dysphagia, weight loss, and generalized weakness. Clinical and imaging investigations revealed a violaceous tumor on the right arm and disseminated metastases affecting the liver, spleen, bones and lymph nodes. A liver biopsy confirmed a small round blue cell neoplasm suggestive for MCC, although immunohistochemistry could not be performed due to the patient’s fulminant deterioration and death within 12 days of admission. Conclusions: This case is notable for its exceptionally rapid progression, particularly splenic involvement, and absence of known immunosuppressive factors. It highlights the existence of highly proliferative MCC subtypes with potential for bypassing classical metastatic pathways. Early clinical suspicion and prompt histological evaluation are essential for diagnosis, although the prognosis remains poor in advanced stages. Due to fulminant deterioration, immunohistochemistry could not be performed; therefore, the diagnosis is highly suggestive based on clinical, imaging, and morphological correlation. Full article

Background/Objectives: Head and neck cutaneous squamous cell carcinoma (HNcSCC) has the potential to metastasize to local lymph nodes, which can significantly impact prognosis. However, the optimal management of patients with clinically node-negative (cN0) disease remains unclear. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines. PubMed, Scopus, CINAHL, and Web of Science databases were searched from inception to 7 August 2025. Two parallel searches were conducted: one to capture management strategies and outcomes of cN0 patients with HNcSCC and one to capture occult nodal metastasis rates of the same population. Results: A total of 38 studies were included. Post-excision management strategies included observation, sentinel lymph node biopsy (SLNB), elective dissection (ED), and elective nodal irradiation. The pooled rate of occult lymph node metastasis was 13.9% in 1673 HNcSCC tumors overall and 12.5% when limited to 977 high-risk tumors. Overall recurrence in the SLNB group (8.3%) was significantly lower than both the observation (16.9%, p < 0.0001) and ED (23.7%, p < 0.0001) groups. Additionally, overall mortality in the SLNB group (6.1%) was significantly lower than observation (29.9%, p < 0.0001) and ED (31.4%, p < 0.0001). Conclusions: We found that SLNB was associated with lower recurrence and mortality compared with observation and ED. While not assumed to be causative, our findings support the role of SLNB in diagnosing occult metastasis and staging disease in this population. Full article

Cutaneous metastases (CMs) represent an uncommon but clinically significant manifestation of advanced malignancies, originating from both solid and non-solid cancers. This review explores the clinical characteristics and prognostic implications of CMs. For solid cancers, CMs are most frequently associated with primary malignancies of the breast, lung, and gastrointestinal tract, presenting as nodules, plaques, or ulcerative lesions. In contrast, CMs from non-solid cancers, such as hematologic malignancies, often exhibit distinct patterns, including diffuse infiltrates or erythematous plaques, mimicking inflammatory dermatoses. Clinical features, as well as dermoscopy, may help, but diagnostic confirmation relies on histopathological evaluation and immunohistochemical studies, which are essential for determining the primary source of the malignancy. Clinically, CMs often signify a poor prognosis, necessitating prompt recognition and tailored management to improve patient outcomes. This comprehensive review aims to enhance clinical understanding and awareness of CMs to facilitate early diagnosis and optimized treatment strategies. Full article