Search Results (91)

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: Cutaneous squamous cell carcinomas (cSCC) of the head and neck district are among the most common non melanocytic malignant skin carcinomas. The proposal to differentiate, within the N stage, parotid metastases from lateral cervical metastases, originates from the different prognostic value of the metastatic region involved. Methods: We retrospectively evaluated 61 patients, surgically treated for parotid metastases from cSCC between January 2002 and June 2023, in four Departments of Surgery, to assess the geographic distribution of parotid metastases and to describe their recurrence patterns, to evaluate the prognostic value of the number of affected lateral cervical lymph nodes (LN) and the number of positive intra-glandular lymph nodes (IGLN) and to identify the main prognostic histopathological factors. Results: Our results did not show significant differences between participating centers in the distribution of parotid metastases, nor in their recurrence rates. However, our results highlight how adjuvant radiotherapy is deeply associated with the Overall Survival (OS), improving survival rates in patients with advanced-stage neoplasms (Odds Ratio 5.0), although causality cannot be inferred because of the retrospective study design. Moreover, a statistically significant correlation was found between the major inflammatory biomarkers and the OS. The presence of IGLN was identified as one of the main factors associated with recurrence and poor prognosis in patients with cSCC and in particular, in patients with N3b nodal stage. Conclusions: our findings suggest that both LN and IGLN could be used to propose an additional staging stratification for the N parameter, thereby guiding the treatment strategy and postoperative follow-up for patients with parotid metastases from cSCC of the head and neck district. Full article

Background and Clinical Significance: Cutaneous squamous cell carcinoma (CSCC) is a common non-melanoma skin cancer, and while most cases are curable, a small proportion progresses to locally advanced or metastatic disease. As neoadjuvant immunotherapy with PD-1 inhibitors such as cemiplimab becomes more widely adopted, understanding real-world patterns of response remains essential. Case Presentation: We report a case of a man in his 50s with a large, locally advanced CSCC of the left hand in whom neoadjuvant cemiplimab was chosen to reduce tumor burden and preserve hand function when margin-negative resection was unlikely. The patient received four cycles of cemiplimab and demonstrated marked clinical improvement followed by complete pathological response at the primary site upon wide local excision. However, metastatic involvement of the epitrochlear and axillary lymph nodes was identified at surgery despite initial benign imaging. Postoperative PET/CT showed no additional disease, and the patient subsequently underwent axillary dissection and adjuvant cemiplimab with good functional recovery. Conclusions: This case highlights the potential for neoadjuvant cemiplimab to achieve substantial local tumor control and functional preservation while emphasizing the need for careful nodal assessment and ongoing surveillance in patients with very-high-risk CSCC. In cases where baseline cross-sectional staging is not performed, pre-existing occult nodal disease cannot be excluded. Full article

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

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

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer diagnosed worldwide after basal cell carcinoma. CSCC represents a growing global public health challenge due to its higher potential of local invasion, recurrence, and metastasis. Incidence rates of cSCC are projected to increase due to rising exposures to risks factors. Ultraviolet light exposure is the primary cause, and lighter skin pigmentation, immunosuppressive conditions and skin phototype are the primary risk factors. CSCC typically presents as a red, scaly, flat lesion (in situ tumors) or a red, firm, raised lesion with scale or erosion (invasive tumors). Surgical excision remains the standard-of-care for localized cSCC and is often curative. Although, most patients achieve favorable outcomes, a subset of cSCC exhibits a highly aggressive and metastatic phenotype (postoperative recurrence rates are approximately 5%). Addressing the clinical challenge posed by these high-risk cases requires a more comprehensive understanding of the underlying molecular drivers. This review examines the interaction between transglutaminase 2 (TG2) and the G-protein-coupled receptor 56 (GPR56) as a pivotal driver of the aggressive cSCC phenotype. This molecular axis is particularly significant for its role in the maintenance of epidermal cancer stem (ECS) cells, which contribute to tumor progression and therapy resistance. While the definitive link between the TG2-GPR56 complex and systemic metastasis in cSCC is currently being elucidated, significant evidence from analogous malignancies and in vitro keratinocyte models provides a clear mechanistic roadmap for its involvement in tumor invasion. Full article

Background: Cutaneous squamous cell carcinoma (cSCC) represents the second most common form of non-melanoma skin malignancy, and, when not amenable to curative surgery or radiotherapy, it is a life-threatening disease. The anti-PD-1 monoclonal antibody cemiplimab has transformed the outcome of advanced or metastatic cSCC, with response rates approaching 50% and sustained benefit beyond three years in clinical trials. Cemiplimab is now the first-line standard of care treatment for advanced disease. Methods: This retrospective observational study included consecutive adult patients with locally advanced (lac) or metastatic (m) cSCC who received cemiplimab (350 mg every three weeks) at the Center for Immuno-Oncology, University Hospital of Siena, Italy, either through an Expanded Access Program or routine clinical practice. Clinical outcome and treatment related adverse events (TRAEs) are reported. Results: Between December 2019 and December 2023, 27 patients (24 male; median age 82 years [range 41–90]) diagnosed with lacSCC (n = 20 [74.0%]) or mcSCC (n = 7 [25.9%]) were treated with cemiplimab as first line therapy and were followed until June 2024. Head and neck were the primary tumor location for 88.8% of patients, followed by trunk (7.4%) and lower extremities (3.7%). All patients had comorbidities, including six patients (22.2%) with hematologic malignancies. With a median follow-up of 31 months (data cut-off June 2024), the ORR was 66.6% (complete response 22.2%) and the disease control rate (DCR) 77.7%. Median progression-free survival (mPFS) and overall survival (mOS) were not reached, while 2-year PFS and OS rates were 65.2% and 71%, respectively. Treatment was well-tolerated, with three (11.1%) patients experiencing grade ≥3 TRAEs, and three patients discontinuing treatment due to TRAEs. Conclusions: Our real-world experience confirms the high rate of durable objective responses, good tolerability and long treatment duration of cemiplimab in elderly and frail cSCC patients as well. Full article

Objectives: Ex vivo confocal laser scanning microscopy (EVCM) is a pioneering diagnostic method that enables fresh tissue samples to be analyzed directly during surgery. For the assessment of non-melanocytic skin cancer (NMSC), including cutaneous squamous cell carcinoma (cSCC), it provides a rapid addition to conventional histology. While previous studies have shown that EVCM reliably identifies the morphological features of cSCCs, quantitative criteria such as tumor thickness have not yet been systematically evaluated. This study investigated whether EVCM can be used to accurately and reproducibly measure the thickness of cSCCs, an important parameter for predicting metastatic risk. Methods: Eighty-two histologically verified cSCCs from different anatomical sites were assessed by the current gold standard of histopathology and EVCM. A statistical comparison of the confocal tumor thickness (CTT) and the histopathological tumor thickness (HTT) was then performed. In addition, it was analyzed how reliable EVCM was in the assignment of cSCCs to the correct tumor thickness category. Results: There was a very high agreement between both methods, evidenced by a Spearman correlation coefficient of 0.94 and a coefficient of determination of 0.859. Overall, 95.1% of the samples were correctly classified into the appropriate tumor thickness category using EVCM. Cohen’s Kappa of 0.90 indicated almost perfect agreement between EVCM and histology. Conclusions: These findings demonstrate that EVCM is a precise and reliable method for determining tumor thickness and the corresponding category in cSCCs. It enables immediate intraoperative assessment of the metastatic risk and preliminary classification of low-risk tumors. Additional studies with larger patient cohorts are required to further validate these results and support clinical implementation. Full article

Background/Objectives: Non-melanoma skin cancer, which includes cutaneous squamous cell carcinoma (cSCC), ranks as the 5th most common cancer globally with high morbidity and more total deaths than melanoma despite having a lower mortality rate. While most cSCC cases can be treated with surgery, locally advanced, metastatic, and high-risk cSCC tumors are associated with a worse prognosis with higher rates of recurrence and require multimodality therapy. However, there is limited data on animal models of cutaneous squamous cell carcinoma for the use of combinatory immunotherapy and radiation. Methods: In this study, spontaneously generated tumors using DMBA/TPA were treated over three weeks with either IgG control, anti-PD1 antibody monotherapy, 8 Gy of localized radiation, or a combination of anti-PD1 and 8 Gy of radiation followed by anti-PD1 therapy. Results: We found that while anti-PD1 therapy showed a trend toward slowed tumor growth compared to controls, this difference was not statistically significant (p = 0.0775), with most mice showing continued tumor progression. Preliminary histological analysis suggested that anti-PD1 treatment increased CD8+ T cell infiltration, and the addition of radiation further enhanced CD8+ responses but added greater variability. A pathologic review revealed that irradiated tumors were associated with fibroblastic spindle-like cell morphology. Conclusions: This animal model represents a potential preclinical model for studying CSCC with limited responses to immunotherapy to understand potential mechanisms of resistance. Full article

MicroRNAs (miRNAs) have emerged as critical post-transcriptional regulators in melanoma and non-melanoma skin cancers (NMSCs), yet their full biological and clinical significance remains incompletely defined. This review synthesizes current evidence on miRNA dysregulation across basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma (MCC), and melanoma, emphasizing their diagnostic, prognostic, and therapeutic relevance. In BCC, distinct miRNA expression signatures differentiate tumor tissue from normal skin and correlate with histopathological subtypes. miR-383-5p, miR-4705, miR-145-5p, and miR-18a show strong diagnostic potential, while downregulation of miR-34a is consistently associated with greater tumor aggressiveness. Subtype-specific profiles further delineate superficial versus infiltrative lesions, highlighting miRNAs as markers of tumor behavior. cSCC similarly demonstrates characteristic miRNA alterations. miR-31 is markedly upregulated during the transition from actinic keratosis to invasive carcinoma, whereas high miR-205 and low miR-203 levels correlate with poor and favorable prognosis, respectively. Regarding MCC, many miRNAs such as miR-375 and miR-182 may present a clinical value for potential biomarkers, as they are upregulated in MCC. Merkel cell carcinoma has also been linked with Merkel cell polyomavirus (MCPyV). Melanoma exhibits a complex miRNA landscape, including oncogenic miR-18a-5p and miR-146a, and tumor-suppressive miR-128-3p. Several miRNAs correlate with metastatic potential, BRAF mutation status, and therapeutic resistance, particularly miR-181a/b, underscoring their potential as predictive biomarkers. Overall, current evidence supports miRNAs as promising diagnostic, prognostic, and predictive biomarkers in cutaneous oncology. Standardized methodologies and large-scale validation remain essential for their integration into routine clinical practice. Full article

Advanced cutaneous squamous cell carcinoma (aCSCC) comprises locally advanced and metastatic disease not amenable to curative surgery or radiotherapy and is associated with substantial morbidity, mortality, and healthcare costs. This narrative review summarizes current knowledge on the epidemiology, biology, clinical presentation, and staging of aCSCC and critically appraises therapeutic strategies with a focus on programmed death 1 (PD-1) blockade. Immune checkpoint inhibitors now represent the main systemic treatment for advanced cSCC, with clinical trials and observational studies reporting response rates around 45–60%, sustained benefit in a subset of patients, and a manageable yet clinically relevant profile of immune-related toxicities. However, outcomes remain heterogeneous, particularly in elderly, comorbid, and immunosuppressed patients. We therefore review established and emerging prognostic determinants spanning clinical, anatomical, histopathological, metabolic, inflammatory, and on-treatment domains. Priorities for biomarker-enriched studies and harmonized real-world registries to enable more refined risk stratification and genuinely personalized, multidisciplinary management of aCSCC are also outlined. Full article

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with incidence steadily increasing due to cumulative ultraviolet (UV) exposure, impaired immune surveillance, and chronic tissue damage. While most cases are effectively managed with surgical excision, a subset progress to locally advanced or metastatic disease, associated with high recurrence rates, limited curative options, and poor prognosis. The introduction of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis has significantly altered the management of advanced cSCC. Cemiplimab and pembrolizumab are now established systemic therapies, producing durable responses in a proportion of patients. These outcomes reflect the typically high tumor mutational burden and immunogenic microenvironment of cSCC. However, therapeutic decision-making remains particularly complex in several high-risk populations, including solid organ transplant recipients at risk of allograft rejection, patients with chronic dermatologic disorders or non-healing wounds that predispose to carcinogenesis, and individuals with rare hereditary syndromes such as recessive dystrophic epidermolysis bullosa. These so-called challenging populations are frequently excluded from pivotal trials, resulting in limited evidence regarding efficacy, safety, and optimal treatment strategies. This review summarizes current evidence on the management of advanced cSCC in high-risk and underserved patient groups, integrating trial data, real-world evidence, and contemporary guidelines. It also highlights key gaps in knowledge and outlines future directions, with particular focus on the interplay between host immune status, tumor biology, and therapeutic response. Full article

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a rising global incidence. Neurotrophins (NTs) and their receptors, including TrkA and CD271, play key roles in epidermal homeostasis and tumor progression. We showed that CD271 expression and function are critical for low- to high-risk progression of cSCC, while TrkA is highly expressed in poorly differentiated tumors. Although NTRK fusions are recognized as oncogenic drivers, the functional impact of TrkA signaling in cSCC remains underexplored. In this study, we investigated the effects of TrkA inhibition, using both the pan-Trk inhibitor K252a and siRNA-mediated silencing, on cSCC cell lines. We evaluated cell growth and invasion in vitro, using 2D and 3D cultures, and in vivo using zebrafish xenografts. TrkA inhibition significantly reduced tumor growth and invasion, with efficacy comparable to standard chemotherapeutics (5-FU, cisplatin). Additionally, TrkA blockade downregulated mitogenic and invasive markers. Importantly, TrkA inhibition enhanced the response to photodynamic therapy in cSCC spheroids. In zebrafish, Trk-targeted interventions reduced metastatic dissemination. These findings highlight TrkA as a key regulator of cSCC survival and metastasis, suggesting its potential as a therapeutic target either alone or in combination with existing treatments. Full article

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a very common skin malignancy of the head and neck area, with a propensity to spread to local lymph nodes. Epithelial-to-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) play a well-documented role in the progression of the disease. In this study, we developed and characterised multicellular tumour spheroids (MCTS) composed of patient-derived metastatic cSCC cell lines—each exhibiting distinct phenotypes—combined with either dermal- or lymph node-derived fibroblasts. We aimed to investigate how these cellular combinations influence MCTS formation, spatial architecture, and invasive behaviour. We hypothesised that the interplay between different cSCC and fibroblast cell combinations would differentially influence spheroid formation and invasion. Methods: Using live-cell microscopy we assessed the spatial architectures specific to each cell line-fibroblast combination and evaluated the expression of EMT and CAF markers. Furthermore, we utilised MCTS in invasion models to investigate associations between the mode of invasion and the EMT phenotype of the cancer cell line. Results: We show that metastatic cSCC/fibroblast MCTS self-organise into distinct spatial architectures. They also invade through collagen in a manner influenced by fibroblasts but dominated by the EMT status of the originating cancer cells. Conclusions: These findings highlight the physiological relevance and utility of MCTS as models for investigating tumour–stroma interactions and invasion dynamics in metastatic cSCC. Full article

Epidermolysis bullosa (EB) is a group of debilitating, genetic skin disorders characterized by excessive skin fragility, blistering, and ulcerations that cause a cyclical wound healing process. EB presents itself in various subtypes, such as EB simplex (EBS), junctional EB (JEB), dystrophic (DEB), and Kindler Syndrome (KS), which all differ in their genetic cause, severity, and harbor different causes of mortality. Of these variants, JEB and DEB are the most severe, with EBS being the mildest form of the disease and KS presenting in extremely rare cases. The JEB variant tends to cause mortality early on in children less than two years of age due to failure to thrive, sepsis from wound infections, and airway obstruction. In the recessive form of DEB (RDEB), cutaneous squamous cell carcinoma (cSCC) is the major cause of death in patients, with one study reporting a mere 4-year survival after the first EB-cSCC diagnosis. Cutaneous SCCs in the setting of RDEB are particularly concerning because they are often more aggressive and show greater metastatic potential, as compared to ultraviolet-induced SCCs. This review aims to explore the pathophysiology of these EB variants as well as their implications for developing cSCCs. It will also discuss elements of the clinical presentation of such lesions in EB patients and the challenges associated with making a definitive diagnosis. Additionally, we will illuminate various diagnostic techniques, current and future management and treatment strategies for both cSCC and EB, and the importance of early screening and education for patients with EB to maximize patient lifespan and quality of life. Full article