Cutaneous Squamous Cell Carcinoma Research Articles

Expression of p16 in Hypertrophic Lichen Planus.

Although cutaneous squamous cell carcinoma (SCC) arising from lichen planus is rare, hypertrophic lichen planus (HLP) accounts for most of these malignant transformations. Although the mechanism of malignant pathogenesis remains unknown, reports of similar premalignant conditions suggest a potential role of tumor suppressor p16. This is the first study to our knowledge to examine p16 expression in HLP in comparison to cutaneous invasive SCC and normal skin and its implications for malignant transformation. p16 immunohistochemistry of HLP (n = 34) was performed alongside location-matched well-differentiated SCC (WDSCC) and normal skin. Percentage of positive cells, nuclear and cytoplasmic staining intensity, and staining distribution patterns were reviewed by 2 Board-certified dermatopathologists. HLP and WDSCC both showed an increased percentage of positive cells compared with normal skin (P < 0.001). Cytoplasmic p16 was overexpressed in HLP compared with WDSCC (P < 0.05). Most cases of HLP and WDSCC demonstrated stronger basal and suprabasal keratinocyte staining with weaker superficial staining. In WDSCC, a predominant pattern of focal cytoplasmic margination of staining along the cellular periphery was observed. Our finding of cytoplasmic p16 overexpression in HLP suggests a potential mechanism of p16-mediated cell cycle dysregulation seen in other premalignant conditions. p16 overexpression seems to be a possible contributor in the malignant transformation of HLP to SCC.

Cutaneous leishmaniasis misdiagnosed as epithelial skin cancer

Cutaneous leishmaniasis, transmitted by sand flies of the genus Phlebotomus, is one of the most important traveler's dermatoses in Germany. In recent years, an increased incidence of the disease has been observed in travelers returning from endemic areas, including the Mediterranean region of Spain and Italy. In these regions, Leishmania infantum belonging to the Leishmania donovani complex is characteristically the most frequently detected pathogen. We herein report two cases of cutaneous leishmaniasis caused by Leishmania infantum with solitary or multilocular lesions, initially misdiagnosed as actinic keratosis and cutaneous squamous cell carcinoma.

Phase I study of intratumoral administration of CV8102 in patients with advanced melanoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the head and neck, or adenoid cystic carcinoma

BackgroundCV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death...

Gut microbiome features associate with immune checkpoint inhibitor response in individuals with non-melanoma skin cancers: an exploratory study.

Immune checkpoint inhibitor (ICI) therapy has yielded revolutionary outcomes among some individuals with skin cancer, but a large percentage of individuals do not benefit from these treatments. The gut microbiota is hypothesized to impact ICI therapy outcomes. However, data on ICI therapy, gut microbiota, and non-melanoma skin cancers are limited. To examine the association of gut microbiota structure and function with non-melanoma skin cancer ICI outcomes, we performed 16S rRNA V1-V2 gene amplicon sequencing of 68 fecal samples collected longitudinally from individuals with basal cell carcinoma (n = 5), Merkel cell carcinoma (n = 5), or cutaneous squamous cell carcinoma (CSCC, n = 11), followed by tumor-dependent differential analyses of bacterial composition and fecal sample analysis by untargeted metabolomics. Across all tumor types, we identified 10 differential bacterial genera between responders (R) or non-responders (NR) to ICI therapy. Among individuals with CSCC, we identified 10 genera and 20 species that differentiated between R and NR and yielded 8 pathways enriched in NR and 12 pathways enriched in R by predicted functional pathway analyses. Untargeted fecal metabolomics to examine putative gut microbiota metabolites associated with CSCC ICI R/NR identified nine KEGG pathways associated with ICI efficacy. In summary, this exploratory study suggests gut microbiota features that are associated with ICI efficacy in individuals with non-melanoma skin cancers and highlights the need for larger studies to validate the results.IMPORTANCEPrior studies examining associations between ICI efficacy and the gut microbiome have focused primarily on individuals with melanoma, for whom ICI therapy was first approved. Meanwhile, data regarding microbiome features associated with ICI responses in individuals with non-melanoma skin cancers (NMSCs) have remained limited. This initial fecal microbiota examination of individuals with NMSCs suggests that larger-scale studies to extend and validate our findings may yield predictive or prognostic biomarkers for individuals with NMSC receiving ICI with potential to provide insight to complementary, effective therapeutic interventions through microbiota modification.

Antibiotics use decreases survival in cutaneous squamous cell carcinoma patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) have become the first-line therapy in patients with advanced cutaneous squamous cell carcinoma (cSCC). Antibiotics (ATB) have been reported to reduce ICI response in cancers, but this has not been evaluated in cSCC. To evaluate ATB exposure at the onset of ICI in cSCC patients and to analyze its impact on outcome. This single-center retrospective study included all patients who started anti-PD-1 for cSCC between March 2019 and July 2023. Exposure to ATB within 3 months prior and after the onset of ICI (ATB 3-3), including patients exposed within 1 month prior and after (ATB 1-1) were recorded. Response to ICI and survival were compared between patients with or without ATB exposure. Among 104 patients included, 45 % were classified into ATB 3-3 subgroup, and 20 % to ATB 1-1. Disease control rate at 3 months were lower in both ATB 1-1 and ATB 3-3 subgroups, compared to their control group (p = 0.02 and 0.03, respectively). The overall survival and disease specific survival were lower in the ATB 1-1 subgroup, compared to control group (p = 0.04 and p = 0.01, respectively). Median progression free survival was 127 days in ATB 1-1 group, significantly lower than the control group (not reached), p = 0.005. ATB intake was very frequent at ICI initiation in cSCC patients. In our cohort, ATB use within 1 month before or after ICI initiation significantly impacted survival, highlighting the need for caution when prescribing antibiotics in this population.

Association of cutaneous immune-related adverse events with improved overall survival among patients with cutaneous squamous cell carcinoma treated with palliative PD-1 inhibition

Association of cutaneous immune-related adverse events with improved overall survival among patients with cutaneous squamous cell carcinoma treated with palliative PD-1 inhibition

257 From skin to bone: a rare case of metastatic cutaneous squamous cell carcinoma

257 From skin to bone: a rare case of metastatic cutaneous squamous cell carcinoma

18 Cutaneous squamous cell carcinoma (Marjolin Ulcers): early identification in old wounds

18 Cutaneous squamous cell carcinoma (Marjolin Ulcers): early identification in old wounds

Pembrolizumab for the Treatment of Locally Advanced Cutaneous Squamous Cell Carcinoma: Patient Selection and Special Considerations.

The treatment of locally advanced cutaneous squamous cell carcinoma (cSCC) has shifted with the advent of immune checkpoint inhibitors (ICIs). Traditional treatment methods have been met with limited efficacy and durability. Recently, ICIs such as pembrolizumab and cemiplimab have emerged as effective alternatives for treating advancedcSCC. Pembrolizumab, approved by the FDA in 2020 for recurrent or metastaticcSCCnot amenable to curative surgery or radiation, has shown promising results in clinical trials. Immunotherapy is also being explored in neoadjuvant settings, with ongoing trials evaluating its potential to improve outcomes for high-risk patients with recurrent or metastatic disease. However, patient selection remains crucial, with the tumor microenvironment playing a key role in predicting treatment response. With many patients achieving a complete response, immunotherapy presents a promising option; however, ongoing research is needed to refine its use, especially in immunocompromised or high-risk patients.

Dysregulation of mRNA expression by hsa-miR-186 overexpression in arsenic-induced skin carcinogenesis.

Dysregulated miRNA expression contributes to development of arsenic-induced cutaneous squamous cell carcinoma (cSCC). hsa-miR-186 (miR-186) is overexpressed in arsenical cSCC tissues as well as in preclinical cell line model of arsenical cSCC. Simultaneous miR-186 overexpression and chronic inorganic trivalent arsenite (iAs; 100nM) exposure transformed human HaCaT cell line preferentially over miR-186 overexpression or iAs exposure alone. Both iAs and miR-186 regulate the expression of wide range of mRNA targets. However, how their interaction impacts the transcriptome-wide mRNA expression landscape ushering in cancer is unknown. We performed longitudinal RNA-seq analysis in passage-matched HaCaT cell clones (±miR-186 overexpression) with simultaneous chronic iAs exposure (0/100nM) at 12 and 29weeks. We determined the impact of each factor and their interaction towards differential gene expression and pathway dysregulation employing two different statistical approaches (t-statistic and 2-factor ANOVA). We show that a core set of pathways are dysregulated deterministically irrespective of the statistical approach chosen, possibly representing necessary changes for transformation. The data suggest that each clonal line could take a unique route to dysregulate this core set of pathways necessary for transformation, highlighting the possible role of stochasticity in cancer development. Evidence is presented to sift the strengths and weaknesses of each statistical methodology in providing biological understanding of events that play crucial roles in carcinogenesis in large datasets with multiple contributing variables.

Milestone events in recessive dystrophic epidermolysis bullosa (RDEB): findings of the PEBLES Study.

In recessive dystrophic epidermolysis bullosa (RDEB), complications like oesophageal strictures, hand contractures, cardiomyopathy and cutaneous squamous cell carcinoma (SCC) may develop, necessitating procedures such as oesophageal dilatation (OD), gastrostomy tube placement and hand surgery. To determine prevalence and age of onset of milestone events by RDEB subtype, specifically dysphagia, first OD, first gastrostomy tube, first hand surgery, cardiomyopathy, first SCC and death. The Prospective Epidermolysis Bullosa Longitudinal Evaluation Study (PEBLES) is a register study of individuals with RDEB which records comprehensive EB- and non-EB-related health information. Age of onset and prevalence of milestone events was analysed as all RDEB and by RDEB subtype. Dysphagia occurred in 89% of 62 total participants including all with severe (RDEB-S) and inversa (RDEB-Inv) subtypes, and OD was also frequent, in 69% overall (92% RDEB-S, 89% RDEB-Inv). All events were most frequent and occurred earliest in RDEB-S (except cardiomyopathy) with median age of dysphagia, OD and gastrostomy tube placement in the first decade. Frequent and early dysphagia and OD in RDEB-Inv may suggest this subtype before characteristic flexural skin changes manifest. Thirty-five percent of RDEB-S participants had a first SCC at median age 27.8 years. Seven participants died in the 10-year study; median age for the 6 with RDEB-S was 36 years and causes included sepsis, metastatic SCC and complications of refeeding syndrome. Our results detail the frequency and prevalence of important milestone events by RDEB subtype, informing prognostication, increasing understanding of RDEB natural history to help inform study endpoints, and potentially serving as proxy control data for future clinical trials.

Surgical Outcomes for Nonmelanoma Skin Cancer of the Head and Neck.

There is no consensus on elective lymphatic dissection of the parotid and neck for nonmelanoma skin cancer (NMSC) due to challenges in detecting occult spread to these regions. This study aimed to summarize clinical data and evaluate correlations between risk factors, nodular metastasis, and the need for elective parotidectomy in patients with cutaneous squamous cell carcinoma (CSCC), Merkel cell carcinoma (MCC), and apocrine carcinoma (AC) of the head and neck, all with clear surgical margins and negative imaging results for regional metastases. We retrospectively reviewed 166 patients with CSCC, one with MCC, and one with AC of the head and neck, all treated surgically between September 2006 and July 2022. The neck and parotid nodes were imaged preoperatively, and nodular metastases were verified by pathological examination. Age, maximum primary tumor dimension, and primary tumor depth were evaluated in patients with and without nodular metastases. Seven patients developed nodular metastases after primary tumor excision. Facial paralysis occurred in three of five patients with parotid spread. Age and primary tumor size differed significantly between patients with and without nodular metastases (P < 0.05). Tumor depth did not differ significantly between these groups (P > 0.50). Negative imaging results of nodular metastases before primary tumor excision and clear margins did not imply exemption from nodular metastases postoperatively. Nodular spread of CSCC is associated with multiple risk factors rather than any single factor. Elective parotidectomy is recommended to prevent facial nerve invasion by occult nodular metastasis in patients with CSCCs with advanced age, large primary tumor size (≥T3), critical tumor locations, and/or pathological types with high metastatic potential.

METTL1 coordinates cutaneous squamous cell carcinoma progression via the m7G modification of the ATF4 mRNA

Methyltransferase-like 1 (METTL1)-mediated m7G modification is a common occurrence in various RNA species, including mRNAs, tRNAs, rRNAs, and miRNAs. Recent evidence suggests that this modification is linked to the development of several cancers, making it a promising target for cancer therapy. However, the specific role of m7G modification in cutaneous squamous cell carcinoma (cSCC) is not well understood. In this study, we observed conspicuously elevated levels of METTL1 in cSCC tumors and cell lines. Inhibiting METTL1 led to reduced survival, migration, invasion, and xenograft tumor growth in cSCC cells. Mechanistically, through a combination of RNA sequencing, m7G methylated immunoprecipitation (MeRIP)-qPCR, and mRNA stability assays, we discovered that METTL1 is responsible for the m7G modification of ATF4 mRNA, leading to increased expression of ATF4. Importantly, we demonstrated that this modification is dependent on the methyltransferase activity of METTL1. Additionally, we observed a positive association between ATF4 expression and METTL1 levels in cSCC tumors. Intriguingly, restoring ATF4 expression in cSCC cells not only promoted glycolysis but also reversed the anti-tumor effects of METTL1 knockdown. In conclusion, our results underscore the critical role of METTL1 and m7G modification in cSCC tumorigenesis, suggesting a promising target for future cSCC therapies.

Outcomes of 100 Squamous Cell Carcinomas of the Upper Limb: 100 Squamous Cell Carcinomas of the Upper Limb.

Rates of recurrence, metastases, and mortality for squamous cell carcinoma (SCC) of the upper limb have not been clearly defined. We aimed to characterize these tumors and assess the long-term outcomes, comparing with current literature. A retrospective review was performed on 100 consecutive primary cutaneous upper limb SCCs managed surgically by a single hand surgeon between 2012 and 2019. Data collection included patient demographics and tumor factors from the electronic patient records. One hundred SCCs were identified in 93 patients. Sixty-six percent of patients were male, and the median age was 80 years. Median follow-up was 25 months. Ninety-seven percent of cases were completely excised. The local recurrence rate was 1%, 2% presented with metastases, 4% developed metastases during follow-up, and the mortality related to SCC was 3% with a 33% overall mortality rate. SCCs of the upper limb behave in a similar manner to those located elsewhere. The local recurrence, metastases, and mortality rates were all low, as such the majority of upper limb SCCs can be managed effectively with a single, low morbidity procedure.Deep margin clearance can be particularly challenging to achieve and an acceptable margin should be considered on an individual basis.

Immune checkpoint inhibitors for children with xeroderma pigmentosum and advanced cutaneous squamous cell carcinoma: A case presentation and brief review

SummaryPatients with xeroderma pigmentosum (XP) frequently develop skin cancers early in life, including cutaneous squamous cell carcinoma (cSCC). The median age of death is 32 years and 60% of XP patients die before the age of 20 years. cSCC in patients with XP exhibits an exceptionally high mutation burden, suggesting a favorable response to immune checkpoint inhibitors (ICIs). We present the case of a 7‐year‐old boy with XP and a large facial cSCC complicated by cervical lymph node metastases. Following a tumor board recommendation, systemic immunotherapy with cemiplimab was initiated. Following therapy, the tumors rapidly and completely regressed. To date, only 10 XP patients worldwide have been reported to receive ICIs for inoperable and/or advanced cSCC, with all cases demonstrating tumor regression under ICI treatment. Among these, three were pediatric cases with XP‐C (one 7‐year‐old and two 6‐year‐old children), one of whom had sarcomatoid cSCC. Incidence and nature of adverse events in XP patients were comparable to those observed in the general population. In line with the previously reported ICI‐treated XP children, the present case confirms that anti‐PD‐1 inhibitors are highly effective in children with XP and advanced cSCC.

Surgical Approaches to Pre-Auricular Cutaneous Squamous Cell Carcinomas Extending to the Temporal Bone.

Standardized surgical approaches to advanced pre-auricular cutaneous squamous cell carcinomas (cSCC) are lacking. Fifty-four patients who underwent lateral temporal bone resection (LTBR) for pre-auricular cSCC were grouped into "Levels" of increasing disease spread. Surgical approaches to achieve negative-margin resection were designed for each Level and replicated on cadaveric specimens. Level 1 extended to the external auditory canal, requiring LTBR ± superficial parotidectomy. Level 2 involved the retromandibular space ± temporomandibular joint, necessitating partial mandibulectomy, in addition to the above. Level 3 and 4 involved the deep parotid, being situated either away from (> 5 mm) or close (≤ 5 mm) to the anterior carotid sheath (ACS), respectively. These tumors require radical parotidectomy, with incorporation of the ACS for Level 4. Level 5 involved the ACS at the skull base and should be treated non-surgically. This Level-based system will hopefully lead to further prospective studies and improvements in outcomes for advanced pre-auricular cSCC.

Skin cancer risk in over 200.000 patients with haematologic malignancies in 30 years; a nationwide population-based study in the Netherlands.

Patients with haematologic malignancies are at increased risk of developing skin cancer and often experience worse skin cancer-related outcomes. However, there is a lack of nationwide, population-based data with long-term follow-up on the incidence and risks of different skin cancer types across all haematologic malignancies. To assess population-based risk estimates for cutaneous squamous cell carcinoma (CSCC), malignant melanoma (MM), Merkel cell carcinoma (MCC), and basal cell carcinoma (BCC) among patients with haematologic malignancies, stratified by skin cancer type and haematologic malignancy subgroup. These estimates can serve as a base for surveillance guidelines and patient education. This nationwide population-based epidemiologic cohort study used data on 210,794 patients diagnosed with a haematologic malignancy between 1989 and 2020 from the Netherlands Cancer Registry (NCR). In addition, data on each type of histopathologically confirmed skin cancer per patient after haematologic malignancy diagnosis was retrieved from the NCR. Patients with a history of skin cancer prior to their haematologic malignancy were excluded. Cumulative incidences, standardized incidence ratio's (SIRs), and absolute excess risks for each of the four skin cancers were calculated and stratified by haematologic malignancy subgroup, age, sex, follow-up, and primary treatment. The overall 10-year cumulative incidence of developing a first skin cancer was 2.6% for CSCC, 0.5% for MM, 0.05% for MCC, and 4.8% for BCC. Compared to the general population, nearly all haematologic malignancy subgroups showed more than a twofold increased risk of CSCC, MM, MCC and BCC. Patients with chronic lymphocytic leukemia (CLL) showed the highest risks for each of the four skin cancers, with SIRs of 4.4 for CSCC, 2.7 for MM, 9.3 for MCC, and 2.6 for BCC. These elevated risks persisted for more than 30 years after haematologic malignancy diagnosis. Patients with all types of haematologic malignancies, and especially those with CLL, have a lifetime increased risk of developing different types of skin cancer. These findings highlight the importance of creating awareness among patients and care providers about this increased risk and promoting sun-protective measures and regular skin self-examinations in this high-risk population.

From actinic keratosis to cutaneous squamous cell carcinoma: the key pathogenesis and treatments

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer, among which 82% arise from actinic keratosis (AK) characterized by lesions of epidermal keratinocyte dysplasia. It is of great significance to uncover the progression mechanisms from AK to cSCC, which will facilitate the early therapeutic intervention of AK before malignant transformation. Thus, more and more studies are trying to ascertain the potential transformation mechanisms through multi-omics, including genetics, transcriptomics, and epigenetics. In this review, we gave an overview of the specific biomarkers and signaling pathways that may be involved in the pathogenesis from AK to cSCC, pointing out future possible molecular therapies for the early intervention of AK and cSCC. We also discussed current interventions on AK and cSCC, together with future perspectives.

Dual-center retrospective cohort analysis of high-risk cutaneous squamous cell carcinoma tumors.

High-risk cutaneous squamous cell carcinoma (hr-cSCC) tumors exhibit aggressive behavior, leading to local recurrence, metastasis, and mortality. The management of hr-cSCC tumors is not well-defined. To clarify the impact of clinical risk factors and management strategies on disease-related outcomes (DROs) in patients with hr-cSCCs. This dual-center retrospective cohort study reviewed patient records from 2007 to 2023, focusing on hr-cSCC tumors classified as high-risk according to two staging systems. 160 adult patients with hr-cSCC were included. Tumors > 2cm were associated with a higher risk of recurrence, metastasis, and mortality, with greater risk for tumors > 4cm. Nonsurgical therapies were linked to higher recurrence and mortality rates compared to surgical monotherapy. Patients whose initial treatment was delayed > 60 days following biopsy had increased incidence of DROs. Other variables associated with at least one DRO included female sex, higher tumor grade, lymphovascular invasion, and advanced AJCC-8 stages. Limitations of this study include its retrospective design, narrow demographics, and variable follow-up times. This study identifies increased tumor diameter, non-surgical treatments, delayed treatment > 60 days after biopsy, female sex, tumor grade, lymphovascular invasion, and advanced tumor stage as significant risk factors for DROs in hr-cSCC. Importantly, our study provides new clarifying evidence that delayed surgical treatment of hr-cSCCs > 60 days after biopsy is associated with elevated incidence of DROs.

Immunosuppression and Outcomes in Patients with Cutaneous Squamous Cell Carcinoma of the Head and Neck.

Cutaneous squamous scell carcinoma (cSCC) is a frequent non-melanoma skin cancer that originates from keratinocytes with increased prevalence. cSCC can be either in situ, as in Bowen's disease, or extended. Advanced age, accumulated sun exposure, light pigmentation, and prior skin cancer diagnosis are all significant risk factors for cSCC. Although most cSCCs can be treated surgically, some recur and metastasize, resulting in death. The role of immune status is not yet determined in the prognosis of these patients. Objective. Immunosuppressed patients are more likely to develop cSCC, which is often characterized by more aggressive, multifocal lesions. This study aimed to determine the risks of mortality in patients with cSCC and immunosuppression versus non immunosuppression and to compare variations in overall survival based on different clinical features. Method. We evaluated clinical cases of patients at "Sfantul Apostol Andrei" Emergency Hospital of Galati, Romania, from 1 March 2018 to 1 April 2024. Subjects in the trial had to be at least 18 years old and have a pathologically confirmed diagnosis of cutaneous head and neck squamous cell carcinoma (cHNSCC). We divided the patients into two different categories based on whether they had immunosuppression. Results. In this cohort of 68 subjects with cSCC, patients with immunosuppression had significantly lower overall survival, as well as lower three- and five-year survival rates compared with those without immunosuppression, even after adjustment for age, sex, stage, and previous surgical treatment. The median survival time for immunosuppressed individuals ranged from 11 to 21 months, varying based on their particular characteristics, and most critically, on the presence of other malignancies, while that of immunocompetent patients ranged from 18 to 51 months. In addition, immune-deficient patients with early-stage disease had a 21-month median survival rate that changed to11 months for advanced-stage cases. In a similar manner, immunocompetent patients with early-stage cancer had a significantly better median survival than those withadvancedstages,43 versus 18months. Our results indicate that immunosuppression is a distinct risk factors associated with a less favorable outcome in patients with cHNSCC.