Search Results (212)

Cutaneous squamous cell carcinoma (cSCC) is an immunogenic malignancy with variable immune infiltration and inconsistent responses to checkpoint blockade. Tumor-infiltrating lymphocytes (TILs) influence tumor progression and therapeutic outcome, yet their phenotypic and functional diversity across disease contexts remains incompletely understood. This review systematically characterizes the TIL landscape in human cSCC. Following PRISMA 2020 guidelines, PubMed and Embase were searched up to May 2025 and restricted to studies evaluating tumor-infiltrating lymphocytes in human cSCC, using the modified Newcatle–Ottawa score to assess risk of bias. Data were synthesized qualitatively given methodological heterogeneity. 48 studies met inclusion criteria. cSCCs exhibited dense CD3⁺ infiltrates composed of cytotoxic (CD8⁺GzmB⁺, Ki-67⁺, CD69⁺) and regulatory (FOXP3⁺, CCR4⁺) subsets. Higher CD8⁺ activity correlated with smaller tumors and longer disease-free survival, whereas FOXP3⁺ enrichment and TGF-β2 signaling promoted immune evasion. Immunosuppressed patients demonstrated diminished CD8⁺ density and clonality. Immune modulation with PD-1/PD-L1 blockade, imiquimod, HPV vaccination, or OX40 stimulation enhanced effector function. The cSCC immune microenvironment reflects a balance between cytotoxic and suppressive factors. Harmonizing multimodal immune profiling and integrating spatial context with systemic immune status may advance both prognostic stratification and therapeutic design. 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

Localized cutaneous squamous cell carcinoma (cSCC) has a favorable prognosis, unlike advanced disease, especially with clinical perineural invasion (PNI), which poses substantial management challenges due to aggressivity and higher recurrence, metastasis, and mortality risks. PNI, a high-risk staging feature, has worse outcomes, particularly when clinically evident rather than incidental. Clinical PNI (cPNI) is evident by clinical symptoms (such as pain, paresthesia, or motor deficits) or radiologic findings, whereas incidental PNI (iPNI) is identified only histologically without associated symptoms or radiologic evidence. PNI remains a novel area with varying practice patterns across institutions. Improving risk stratification and tailoring multidisciplinary approaches are critical for optimizing outcomes. Our review outlines clinical practice patterns at our institution, providing insights into managing cSCC with PNI, focusing on diagnosis, imaging, staging, and emerging immunotherapies. A structured search was conducted using the terms “perineural invasion,” “cutaneous squamous cell carcinoma,” and “immunotherapy.” cPNI has a poor prognosis and requires nuanced clinical decision-making. Surgery and radiation remain central to management. Adjuvant therapy offers substantial survival benefit in cSCC with PNI, with improved disease-free and overall survival compared with surgery alone, supporting its use in appropriately selected high-risk patients. Traditional systemic therapies, including cisplatin and cetuximab, remain foundational but have shown only moderate response rates and limited durability in advanced or neurotropic cSCC. In contrast, immunotherapy—now preferred for advanced or unresectable cases—has transformed management, with programmed cell death protein-1 (PD-1) inhibitors showing promising results (up to 69% response rate) and disease stabilization. Neoadjuvant immunotherapy may enable tumor downstaging, improve radiation planning, and reduce surgical morbidity. Imaging for squamous cell carcinoma (SCC) with PNI aids staging and surveillance, but symptoms remain key for detecting recurrence. Our multidisciplinary approach emphasizes personalized care. Larger trials are needed to define the optimal role and sequencing of immunotherapy in this high-risk patient population. Full article

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer after basal cell carcinoma. When squamous cell carcinomas in situ are included, nonmelanoma skin cancer incidence is nearly equal between CSCC and basal cell carcinoma. The incidence of CSCC has been increasing worldwide in recent decades, and despite the effectiveness of office-based therapies, patients with high-risk lesions associated with advanced CSCC face high rates of recurrence and mortality. This underscores the importance of accurate diagnoses and clear criteria to define high-risk lesions for prognosis and better treatment strategies. However, variability exists in CSCC registration practices internationally, and differences in pathology reporting likely contribute to an underestimate of the true burden of disease. Thus, there is a need to refine elements included in skin biopsy reports to provide a precise representation of the high-risk features of CSCC to improve patient care. In this review, a multidisciplinary group of Canadian experts discuss clinical considerations and provide key guidance and practical strategies surrounding skin biopsy techniques, completion of requisition forms, and dermatopathology reports for CSCC. This article summarizes the expert panel’s recommendations with the goal of improving diagnosis and pathological reporting of biopsy specimens to achieve better patient outcomes for CSCC. 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 malignancy in the world, representing approximately 20% of all skin cancers. Immunosuppression is a well-established risk factor, contributing not only to the development of new cSCC lesions but also to more aggressive disease and increased mortality. Despite the National Comprehensive Cancer Network (NCCN) and the American Joint Committee on Cancer (AJCC) 8th edition updates recognizing immunosuppression as a risk factor for cSCC, standardized management protocols for these high-risk patients remain limited. As a result, treatment of this already high-risk group remains a significant challenge and highlights the need for dedicated research and attention to improve outcomes in this patient population. This review explores the current knowledge regarding cSCC in IS patients, outlines key gaps in the knowledge, and highlights recent clinical trials to further guide the evaluation and management of these patients. 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

Background: The mitogen-activated protein kinase (MAPK) signaling pathway is frequently dysregulated in cutaneous squamous cell carcinoma (cSCC). Tumor progression locus 2 (Tpl2), a serine/threonine protein kinase within the MAPK family, regulates cellular proliferation, survival, and inflammatory responses. Loss of Tpl2 activates compensatory signaling cascades, driving increased papilloma and cSCC development. In this study we examined whether dysregulated ErbB signaling contributes to the enhanced tumor burden found in Tpl2^−/− mice. Methods: To evaluate whether aberrant ErbB signaling drives tumorigenesis in Tpl2^−/− mice, wild-type (Tpl2^+/+) and Tpl2^−/− mice were subjected to a two-stage chemical carcinogenesis protocol for 48 weeks. A subset of mice received Gefitinib (an EGFR inhibitor) or Lapatinib (a HER2 inhibitor) in their diet. Results: We found that Tpl2 ablation increases gene expression of EGFR, HER2, and HER3, while baseline protein levels remain unchanged between Tpl2 genotypes. To investigate the possibility of microRNA (miR)-mediated post-transcriptional regulation of EGFR, HER2, and HER3, we measured ErbB-related miR expression in keratinocytes. We found that HER2/3-related miRs 205 and 21 are increased in Tpl2^−/− keratinocytes. Further, Tpl2 loss enhances p-EGFR, EGFR, and HER2 protein expression in papillomas. and HER2-related microRNAs (miRs) 205 and 21 in keratinocytes, and enhances p-EGFR, EGFR, and HER2 protein expression in papillomas. Tpl2^−/− mice developed 12-fold more papillomas and 4-fold more cSCCs compared to Tpl2^+/+ animals. Treatment with Gefitinib or Lapatinib reduced papilloma numbers by 88% and 50%, respectively, while restoring cSCC numbers to Tpl2^+/+ levels. Conclusions: These findings indicate that ErbB targeting represents a promising therapeutic strategy for cSCCs arising from MAPK pathway dysregulation. 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

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

Background/Objectives: Non-melanoma skin cancer (NMSC) is the most common malignancy globally, with cutaneous squamous cell carcinoma (cSCC) posing a significant risk of regional metastasis, especially in high-risk anatomical areas such as the head and neck. While general risk factors for metastasis are well known, few studies have directly compared the clinical and pathological features of synchronous versus metachronous metastatic behavior. This study aimed to evaluate the clinicopathological characteristics and reconstructive implications associated with these two metastatic patterns in head and neck NMSC. Methods: We conducted a retrospective observational study of 46 patients with histologically confirmed metastatic NMSC of the head and neck, treated between January 2022 and May 2024 at a tertiary care center. Patients were stratified into synchronous or metachronous metastasis groups. Clinical data, histopathological features, metastatic sites, and surgical approaches were analyzed. Comparative statistics were applied using chi-square and t-tests, with significance set at p < 0.05. Results: Of the 46 patients, 50% had synchronous and 50% had metachronous metastases. The lower lip was the most common primary tumor site in both groups. Perineural and lymphovascular invasion were more frequent in synchronous metastases. Metachronous cases often required more complex reconstructive procedures, including free flap reconstructions and mandibular resections. Patients with metachronous metastases were significantly older (p = 0.024), and approximately one-third developed metastases more than four years after initial treatment. Conclusions: Head and neck NMSC, particularly involving the lower lip, may exhibit late-onset metastatic potential. Risk-adapted surveillance extending beyond current guidelines is warranted to improve long-term outcomes in high-risk patients. Full article