Cutaneous Squamous Cell Carcinoma Research Articles

Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma

We previously showed that inhibition of glycolysis in cutaneous squamous cell carcinoma (SCC)–initiating cells had no effect on tumorigenesis, despite the perceived requirement of the Warburg effect, which was thought to drive carcinogenesis. Instead, these SCCs were metabolically flexible and sustained growth through glutaminolysis, another metabolic process frequently implicated to fuel tumorigenesis in various cancers. Here, we focused on glutaminolysis and genetically blocked this process through glutaminase (GLS) deletion in SCC cells of origin. Genetic deletion of GLS had little effect on tumorigenesis due to the up-regulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We went on to show that posttranscriptional regulation of nutrient transporters appears to mediate metabolic flexibility in this SCC model. To define the limits of this flexibility, we genetically blocked both glycolysis and glutaminolysis simultaneously and found the abrogation of both of these carbon utilization pathways was enough to prevent both papilloma and frank carcinoma.

The role of cornulin (CRNN) in the progression of cutaneous squamous cell carcinoma involving AKT activation in SCL-1.

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer that has been on the rise in recent times, particularly among older individuals. Cornulin (CRNN) is increasingly recognized as an oncogene involved in developing various types of tumors. However, the precise contribution to cSCC remains unclear. Our study observed a significant increase in CRNN expression in cSCC samples compared to healthy skin. CRNN expression in the SCL-1 cell line derived from cSCC was reduced, leading to a halt in cell growth during the transition from the G1 phase to the S phase. This reduction inhibits cell division, promotes cell death, and decreases cell invasion and migration. CRNN overexpression has been found to enhance cell growth and prevent cells from undergoing natural cell death, and the cancer-promoting effects of CRNN are linked to AKT activation. Using a mouse xenograft model, we demonstrated that the inhibition of CRNN led to a decline in cSCC tumor growth in a living organism, providing evidence of CRNN's involvement in cSCC occurrence and development. This study establishes a foundation for evaluating the effectiveness of CRNN in treating cSCC, enabling further investigation in this area.

D2-40 and CK17 Immunohistochemistry as a Diagnostic Adjunct for HPV-Independent Squamous Lesions in the Vulva and Their Role in Defining Atypical Lichen Sclerosus.

Vulvar lichen sclerosus (LS) is a common, chronic inflammatory disorder with a subset of cases progressing to differentiated vulvar intraepithelial neoplasia (dVIN) and/or squamous cell carcinoma (SCC). Histopathologic diagnosis of LS and dVIN can be challenging, and it is difficult to predict the subset of LS cases that progress. Immunohistochemistry (IHC) may be a useful diagnostic aid in this setting. CK17 has been shown to be overexpressed in invasive SCC and dVIN, and less commonly in LS. Similar to CK17, D2-40 has been correlated with cutaneous SCC prognosis but has not been evaluated in vulvar lesions. We identified a total of 13 patients with HPV-independent vulvar SCC that had precursor LS or dVIN. CK17 and D2-40 IHC stain intensity and pattern was scored in foci of LS, dVIN, and SCC. An increase in basal layer D2-40 expression was observed with progression from LS to dVIN with strong and diffuse staining in SCC. CK17 maintained similar stain intensity among squamous lesions, but displayed different patterns of staining, with superficial staining in LS, suprabasal staining in dVIN, and diffuse staining in SCC. A subset of LS cases displayed an intermediate (suprabasal) CK17 IHC profile, wild-type p53 expression, and cytomorphologic and architectural features intermediate between LS and dVIN; we defined such cases as "atypical LS." We found that a panel of D2-40/CK17 can serve as a diagnostic adjunct to differentiate LS, dVIN, and invasive SCC. Additional studies with larger patient cohorts are needed to validate these findings and determine their prognostic significance.

Mycosis Fungoides and Associated Malignancies in a Dutch Nationwide Retrospective Cohort Study.

The prognosis of patients with mycosis fungoides is variable. As the current literature is scarce and shows mixed results this study investigates the incidence of other primary malignancies in mycosis fungoides patients. A retrospective, nationwide, population- based cohort study was performed with patients with mycosis fungoides between 2000 and 2020 in The Netherlands. All histopathology reports were requested from the Nationwide Network and Registry of Histo- and Cytopathology and screened for other primary malignancies. Lifelong incidence rates were used to compare the incidence of malignancies in mycosis fungoides patients and the general population. In total 1,024 patients were included with a mean follow-up of 10 years (SD 6). A total of 294 cases of other primary malignancies were found with 29% of the mycosis fungoides patients developing at least 1 other primary malignancy. Only cutaneous (odds ratio [OR] 2.54; CI 2.0-3.2) and haematological malignancies (OR 2.62; CI 2.00-3.42) had a statistically significant higher incidence than the Dutch population overall. Mycosis fungoides patients have a significantly increased risk of developing melanomas (OR 2.76; CI 2.11-3.59) and cutaneous squamous cell carcinomas mycosis fungoides (OR 2.34; CI 1.58-3.45). This study shows no association between mycosis fungoides and other solid organ tumours; however, such patients are significantly at risk of developing other haematological and cutaneous malignancies. Clinicians should be aware of this increased risk.

A case controlled study of risk factors for metastatic squamous cell carcinoma in organ transplant recipients: single academic medical center.

Solid organ transplant recipients (SOTRs) are at high risk of cutaneous squamous cell carcinoma (cSCC) metastasis. Despite prior studies identifying risk factors, mortality remains high. Understanding additional risk factors may aid in reducing mortality in this population. This study aimed to investigate risk factors and predictive variables for metastatic cSCC in SOTRs. The primary goal was to accurately identify transplant patients at increased risk of metastatic cSCC. A retrospective case-control study in a single institution of 3576 cases of organ transplants were identified from January 1991 to July 2022. A cohort of metastatic cancer patients and two randomly generated age and organ matched control cohorts were identified. 16 SOTR patients developed metastatic cSCC. The majority were male, with high-risk tumor sites. Tumor depth varied and half exhibited perineural invasion. Cylex® (p = 0.05) and white blood cell counts (p = 0.04) were significantly lower in these patients compared to control. Lung transplants were at highest risk relative to other solid organ transplants. Voriconazole exposure was also associated with increased metastatic risk (p = 0.04). Small sample size at a single institution. Close monitoring of SOTR, especially those with lung transplants given their increased risk, reducing immunosuppression, and limiting exposure to voriconazole can improve outcomes in SOTRs with metastatic cSCC.

Current Advances and Challenges in the Management of Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patients

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and poses a significant risk to immunosuppressed patients, such as solid organ transplant recipients and those with hematopoietic malignancies, who are up to 100 times more likely to develop cSCC compared with the general population. This review summarizes the current state of treatment for cSCC in immunosuppressed patients, focusing on prevention, prophylaxis, surgical and non-surgical treatments, and emerging therapies. Preventative measures, including high-SPF sunscreen and prophylactic retinoids, are crucial for reducing cSCC incidence in these patients. Adjusting immunosuppressive regimens, particularly favoring mTOR inhibitors over calcineurin inhibitors, has been shown to lower cSCC risk. Surgical excision and Mohs micrographic surgery remain the primary treatments, with adjuvant radiation therapy recommended for high-risk cases. Traditional chemotherapy and targeted therapies like EGFR inhibitors have been utilized, though their efficacy varies. Immunotherapy, particularly with agents like cemiplimab and pembrolizumab, has shown promise, but its use in immunosuppressed patients requires further investigation due to potential risks of organ rejection and exacerbation of underlying conditions. Treatment of cSCC in immunosuppressed patients is multifaceted, involving preventive strategies, tailored surgical approaches, and cautious use of systemic therapies. While immunotherapy has emerged as a promising option, its application in immunosuppressed populations necessitates further research to optimize safety and efficacy. Future studies should focus on the integration of personalized medicine and combination therapies to improve outcomes for this vulnerable patient group.

Grover's Disease Association with Cutaneous Keratinocyte Cancers: More than a Coincidence?

Better mechanistic understanding of desmosome disruption and acantholysis in Grover's disease (GD) may improve management of this disease. Recent molecular studies highlighted promising pathways to be explored by directly comparing GD and selected features of associated skin diseases. The association between GD and cutaneous keratinocyte carcinomas, the most prevalent non-melanoma skin cancers (NMSC), is not completely characterized. To review the medical literature regarding GD-associated cutaneous keratinocyte cancers, focusing on molecular features, pathophysiological mechanisms, and disease associations, to help guide future research and patient management. GD has been associated with a variety of skin conditions, but its association with skin cancers has been rarely reported. Between 1983 and 2024, only nine scientific papers presented data supporting this association. Interestingly, we found that GD may mimic multiple NMSCs, as few authors reported GD cases misdiagnosed as multiple cutaneous squamous cell carcinomas for more than 4 years or the presence of superficial basal cell carcinoma-like areas associated with focal acantholysis. In conclusion: (a) GD may be an imitator of multiple NMSCs, and (b) the relationship between GD and NMSCs may reveal promising pathways for the mechanistic understanding of desmosome disruption and acantholysis in GD and may even lead to its reclassification as a distinctive syndrome.

Cutaneous Squamous Cell Carcinoma in Patients with Solid-Organ-Transplant-Associated Immunosuppression.

The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.

Predicting adjuvant radiation therapy benefit in cutaneous squamous cell carcinoma with the 40-gene expression profile.

Aim: To independently confirm that the 40-gene expression profile (40-GEP) test can identify patients with high-risk cutaneous squamous cell carcinoma who are more or less likely to benefit from adjuvant radiation therapy (ART).Materials & methods: Primary cutaneous squamous cell carcinoma tumors from two academic centers received retrospective 40-GEP testing and were analyzed for 5-year metastasis-free survival and projected time to event.Results: Random sampling of matched patient pairs (n=52 ART-treated; 371no ART) showed a median 50% decrease in 5-year progression rate for ART-treated patients (vs no ART) with 40-GEP Class 2B. Class 2A was associated with a modest ART benefit, but not Class 1.Conclusion: The 40-GEP identified patients most likely to benefit from ART (Class 2B) and those that can consider deferring treatment (Class 1).

Photographic scale for the characterization of actinic keratosis through reflectance confocal microscopy: a quantitative approach to cellular transformation.

Actinic keratosis (AK) is a highly prevalent pre-cancerous skin lesion that often leads to cutaneous squamous cell carcinoma. There are different stages of evolution of the disease and several features that characterize keratosis. This study aimed to develop a qualitative and quantitative visual diagnostic tool to facilitate the identification of the characteristics and severity of the main cellular attributes of AK and to show its applicability in evaluating the evolution or treatment through image analysis. Literature research on the main scientific databases and in the institute's database was carried out to gather all the different levels of cellular transformation. To validate the scale, a preliminary characterization study was carried out with 21 subjects who had clinically diagnosed AK lesions to classify the attributes in each skin layer and test the accuracy of the diagnosis of the scale. Afterward, and to show the possibility of a follow-up with a topical treatment, the subjects were divided into two treatment groups, receiving either a cream formulation containing retinoic acid, or a placebo formula. The evaluation was carried out through confocal reflectance microscopy and a digital camera with dermoscopic quality before and after 90 days of treatment. A table detailing the 18 attributes of AK, and a photographic scale containing RCM images graded by scores established for each characteristic and the frequency of spreading were developed. The results of the validation presented good repeatability, correlation with clinical evaluation, and capacity for differentiating treatments demonstrated by the significant improvement after topical treatment by the reduction of the score for 10 out of the 18 attributes. The preliminary study, evaluated by the detailed transformation scale highlights important differences in the subclinical approach that allows a deeper evaluation of the aspects of the lesion's re-incidence even after fully treated skin sites. This study brings an innovative method based on RCM, to assist in the quantification of cell transformation level, provide early diagnosis, and deliver a powerful treatment evaluation tool to provide smoother treatment, as well as prevent re-incidence in the cases.

RBM3 Inhibits the Cell Cycle of Cutaneous Squamous Cell Carcinoma through the PI3K/AKT Signaling Pathway.

RBM3 is a key RNA-binding protein that has been implicated in various cellular processes, including cell proliferation and cell cycle regulation. However, its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. We aimed to investigate the expression levels of RNA-binding motif protein 3 (RBM3) in patients with cSCC and evaluate its effect on cell ability in cSCC and its underlying regulatory mechanisms. The expression of RBM3 in cSCC tissues and A431 cells was determined via immunohistochemistry and western blotting. Plenti-CMV-RBM3- Puro was used to overexpress RBM3. The effect of RBM3 on the proliferation ability of cSCC cells was evaluated using MTT and colony formation assay. Cell apoptosis and cell cycle were determined using flow cytometry, while the protein expressions of BAX, NF-κB, BCL2, CASPASE 3, CYCLIN B, CYCLIN E, CDK1, phosphorylated (P)-CDK1, CDK2, P-CDK2, ERK, P-ERK, P-AMPK, AKT, P-AKT, MDM2, and P53 were assessed using western blotting. RBM3 expression was significantly downregulated in cSCC tissues and A431 cells. RBM3 overexpression significantly inhibited the cell proliferation and colony formation ability of A431. Notably, RNA-seq results showed that the differentially expressed genes associated with RBM3 were primarily involved in the regulation of the cell cycle, oocyte meiosis, and P53 signaling pathway, as well as the modulation of the MAPK, AMPK, Hippo, mTOR, PI3K/AKT, Wnt, FoxO, and NF-κB signaling pathways. Additionally, our findings demonstrated that overexpression of RBM3 inhibited cell proliferation and induced cell cycle arrest of cSCC through modulation of the PI3K/AKT signaling pathway. This study provides novel insights into the suppressive roles of RBM3 in cell proliferation and the cell cycle in cSCC and highlights its therapeutic potential for cSCC.

The Free Flap Reconstruction of Facial Defects after Squamous Cell Carcinoma Excision

Background and Objectives: Cutaneous squamous cell carcinoma is the second most common skin cancer. There are many methods for the reconstruction of facial subunit defects after skin cancer excision. The face is vital to a person’s life and should be reconstructed considering functional and aesthetic aspects. Despite a variety of flap types and techniques, it is still challenging to meet the various demands. The aim of this study was to compare free flaps for facial reconstruction after resection of cutaneous squamous cell carcinoma. Materials and Methods: This study included 14 patients from January 2021 to June 2023. Patients who underwent facial SCC resection and subsequent reconstruction using free flaps were analyzed retrospectively. Age, sex, and localization were recorded. Follow-ups ranged from 5 to 21 months, with an average of 13 months. Results: All free flaps survived well except one case of partial flap necrosis. In most patients, good to excellent functional and aesthetic results were obtained. The donor site healed uneventfully in all patients. Conclusions: Free flap reconstruction is an excellent choice in wide skin oncologic defects. In terms of texture, it also could be a good surgical method. The use of a fraxel laser can progressively facilitate improved color matching with the surrounding skin.

Successful Use of Cemiplimab in a Very Elderly Patient With Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (SCC) is a common skin cancer with significant morbidity and mortality, particularly in advanced stages. Treatment options for metastatic cutaneous SCC in very elderly patients are limited due to concerns about treatment tolerability and potential adverse effects. We report the case of a 90-year-old female patient with metastatic cutaneous SCC who was treated with cemiplimab, a monoclonal antibody (m-Ab) against programmed cell death protein 1 (PD-1), in combination with radiotherapy. The patient received cemiplimab for a limited period, during which time she demonstrated significant clinical improvement without severe adverse events. Radiotherapy was performed as a locoregional treatment with the aim to enhance immunotherapy efficacy. This case highlights the feasibility and effectiveness of cemiplimab in very elderly patients with metastatic cutaneous SCC. Despite the common apprehensions regarding the use of immunotherapy in this age group, our patient tolerated cemiplimab well, and the combination with radiotherapy proved beneficial. This suggests that even in very elderly patients, short-term use of cemiplimab, in conjunction with locoregional treatments such as radiotherapy, can be a viable and successful therapeutic approach. Cemiplimab, even in combination with radiotherapy, can be effectively and safely administered to very elderly patients with metastatic cutaneous SCC. This case supports the consideration of immunotherapy, even for a limited duration, as a practical option in the management of advanced cutaneous SCC in elderly patients, expanding the potential treatment strategies for this population.

The promotion of cell proliferation and invasion in cutaneous squamous cell carcinomas after ARNT downregulation is associated with CXCL3

The promotion of cell proliferation and invasion in cutaneous squamous cell carcinomas after ARNT downregulation is associated with CXCL3

940TiP INTerpath-007: A phase II/III, adaptive, randomized study of neoadjuvant and adjuvant pembrolizumab (pembro) with V940 (mRNA-4157) for treatment of resectable locally advanced (LA) cutaneous squamous cell carcinoma (cSCC)

940TiP INTerpath-007: A phase II/III, adaptive, randomized study of neoadjuvant and adjuvant pembrolizumab (pembro) with V940 (mRNA-4157) for treatment of resectable locally advanced (LA) cutaneous squamous cell carcinoma (cSCC)

Cancer and Hidradenitis Suppurativa

Hidradenitis suppurativa patients have an increased risk of developing cancer. This includes not only hematologic malignancies and solid tumors, but also cutaneous squamous cell carcinoma originating within the hidradenitis suppurativa lesions. The development of squamous cell carcinoma is most commonly associated with Caucasian men who smoke and have severe gluteal or perianal lesions of more than 25 years duration. Other factors that have occasionally been associated with hidradenitis suppurativa-related squamous cell carcinoma include treatment with a tumor necrosis factor-alpha inhibitor (such as infliximab and adalimumab), genodermatoses (such as keratitis-ichthyosis-deafness syndrome and Dowling-Degos disease), and paraneoplastic syndromes (such as hypercalcemia, hypercalcemia-leukocytosis, and paraneoplastic neuropathy). The tumor may demonstrate the presence of human papillomavirus; even after treatment, patients have a poor prognosis since cancer metastasis, or recurrence, or both commonly occurs. The potential role of human papillomavirus vaccination for cancer prevention and early treatment of squamous cell carcinoma with targeted therapy (with an epidermal growth factor inhibitor such as cetuximab) and/or checkpoint inhibitor immunotherapy (such as cemiplimab and pembrolizumab) remains to be determined. Rarely, hidradenitis suppurativa lesions have mimicked cutaneous metastases in patients with visceral malignancy by demonstrating an increased uptake of fluorine-18 fluorodeoxyglucose on positron emission tomography and/or computerized tomography scans. Also, both primary cancers (such as cutaneous squamous cell carcinoma and mucinous adenocarcinoma) and breast cancer skin metastases can masquerade as hidradenitis suppurativa lesions. Therefore, when a lesion is located at a current or prior site of hidradenitis suppurativa that is new or rapidly growing and/or does not respond to hidradenitis suppurativa-directed therapy, prompt evaluation to establish or exclude the diagnosis of cancer should be considered.

1091P Neoadjuvant cemiplimab for stage II–IV cutaneous squamous cell carcinoma (CSCC): 2-year follow-up and biomarker analyses

1091P Neoadjuvant cemiplimab for stage II–IV cutaneous squamous cell carcinoma (CSCC): 2-year follow-up and biomarker analyses

49977 The regulatory roles of Syk in cell death of cutaneous squamous cell carcinoma cells

49977 The regulatory roles of Syk in cell death of cutaneous squamous cell carcinoma cells

53535 Integrative Analysis of Intermediate-to-High Risk Cutaneous Squamous Cell Carcinoma (cSCC)

53535 Integrative Analysis of Intermediate-to-High Risk Cutaneous Squamous Cell Carcinoma (cSCC)

49464 Use of Imaging in Cutaneous Squamous Cell Carcinoma to Detect High-Risk Tumor Features, Nodal Metastasis, and Distant Metastasis: A Systematic Review

49464 Use of Imaging in Cutaneous Squamous Cell Carcinoma to Detect High-Risk Tumor Features, Nodal Metastasis, and Distant Metastasis: A Systematic Review