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Simple Summary: Immunosuppression is strongly associated with an increased risk of developing cutaneous squamous cell carcinoma (cSCC). Compared to controls, immunosuppressed patients demonstrated Several differences were seen between immunosuppressed (IS) patients and the control group. Lower survival rates, higher recurrence rates, multiple (malignant) primary tumors, and higher rates of positive margins were seen in IS patients compared to immunocompetent controls. Among immunosuppressed patients and solid organ transplant recipients (SOTR), patients with chronic lymphocytic leukemia (CLL), chronic kidney disease (CKD), rheumatoid arthritis (RA) and psoriasis demonstrated worse outcomes compared to controls and to other immunosuppressed groups. Active surveillance and close follow-ups by both primary oncologists and dermatologists are advised in order to diagnose and treat cSCC at an early stage. Background: Immunosuppression is strongly associated with an increased risk of developing cutaneous squamous cell carcinoma (cSCC). Studies on solid organ transplant recipients (SOTR) and chronic lymphocytic leukemia (CLL) patients have already demonstrated higher rates of aggressive cSCC tumors in these populations compared to immunocompetent controls. Studies on other immunosuppressed patient groups are scarce. This study was aimed at assessing the effects of different immunomodulating conditions on patients diagnosed with cSCC. We sought to compare the clinical features, treatments, and survival rates among the different study groups, as well as outcomes to those of immunocompetent controls with cSCC. Methods: A retrospective analysis of 465 cSCC patients, both immunosuppressed (IS) and immunocompetent controls. Etiologies for immunosuppression included SOTR, CLL, chronic kidney disease (CKD), psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). Results: Compared to the control group, IS patients demonstrated several significant differences. These include higher rates of positive resection margins, higher recurrence rates, and multiple SCC tumors. Patients in the IS group, who were also given immunomodulating agents, demonstrated even lower survival rates. Cox regression analysis demonstrated statistically significant decreased overall survival (OS) rates for IS patients compared to the controls (OR = 1.9, p = 0.031). SOTR patients tend to have multiple cSCC tumors (35%), with the highest number of primary tumors compared to controls (2.54 tumors per patient on average, p < 0.001), but also compared to all other IS groups. The average SCC lesion size in the SOTR group was the smallest, measuring at 13.5 mm, compared to the control group and all other IS groups. Decreased survival rates were seen on Cox regression analysis compared to controls (HR = 2.4, p = 0.001), but also to all other IS groups. CLL patients also had the highest rates of positive margins compared to controls (36% vs. 9%, p < 0.01) and to all other IS groups. They were also most likely to get adjuvant or definitive oncological treatments, either radiotherapy or chemotherapy, compared to controls (36% vs. 15%, p = 0.02) and to other IS groups. Patients in the CKD group demonstrated the highest rates for multiple cSCC (OR = 4.7, p = 0.001) and the worst rates of survival on Cox regression analysis (HR = 3.2, p = 0.001). Both rheumatoid arthritis and psoriasis patients demonstrated the shortest disease-free survival rates (2.9y ± 1.1, 2.3y ± 0.7, respectively), compared to controls (4.1y ± 2.8) and to all other IS groups. Conclusions: Among cSCC patients, immunosuppression due to SOTR, CLL, CKD, RA, and psoriasis is associated with worse outcomes compared to controls and other IS groups. These patients should be regarded as high-risk for developing aggressive cSCC tumors. This study is the first to assess and compare cSCC outcomes among multiple IS patient groups. [ABSTRACT FROM AUTHOR]

Objectives: The use of stereotactic body radiation therapy (SBRT) has not been assessed in advanced-stage feline solar-induced facial squamous cell carcinomas (SCCs). The objective of this study was to provide preliminary data on the use and safety profile of coarse fractions administered with an SBRT regime to manage advanced-stage feline solar-induced facial SCCs. Methods: This retrospective study assessed five cats diagnosed with advanced-stage solar-induced facial SCCs that received SBRT as their primary treatment or, in one cat, following failed surgical intervention. Tumour sites received three fractions totalling 26.25–27 Gy over a 3–5-day period. Results: All patients developed acute effects following SBRT including alopecia, epilation and erythema. Late effects were mild and included alopecia, variable pigmentation and leukotrichia within radiation fields. All patients were alive at the time of article submission, with overall survival times ranging from 118 to 991 days. Conclusions and relevance: The results suggest that coarse fractions administered with an SBRT technique is a safe and effective treatment tool for the management of advanced-stage feline solar-induced facial SCCs. These data provide preliminary evidence to support larger, prospective studies evaluating the management of feline facial SCCs with SBRT. [ABSTRACT FROM AUTHOR]

Aryl hydrocarbon receptor (AhR) provides a deeper insight into the pathogenesis of cutaneous squamous cell carcinoma (cSCC). AhR ligands, such as 6-formylindolo[3,2-b] carbazole (FICZ), and 7,12-Dimethylbenz[a]anthracene (DMBA), constitute major substrates for the cytochrome P450 (CYP) family, and influence the expression of various cytokine genes, including IL-17 and IL-23-related genes via the AhR. On the other hand, proinflammatory cytokines could drive tumor progression through the TRAF-ERK5 signaling pathway in cSCC. From the above findings, we hypothesized that AhR ligands might enhance the mRNA expression of proinflammatory cytokines via the AhR, leading to the development of cSCC. The purpose of this study was to investigate (1) the immunomodulatory effects of FICZ and DMBA on normal human keratinocytes (NHKCs), focusing on IL-17, and related cytokines/chemokines (IL-23, IL-36γ, and CCL20), (2) the expression of these factors in AhR-dependent pathways using a two-stage chemically induced skin carcinogenesis mouse model, and (3) the expression of these factors in lesion-affected skin in cSCC. Both FICZ and DMBA augmented the expression of CYP1A1, p19, CCL20, and IL-36γ mRNA in NHKCs in vitro. Moreover, the mRNA expression of these proinflammatory factors, as well as IL-17, in mouse cSCC is significantly decreased in the AhR-(fl/fl) Krt5-(Cre) mice compared to wild type mice, leading to a decrease in the number of developed cSCC lesions. Furthermore, CCL20, IL-23, as well as IL-17, are detected in the lesion-affected skin of cSCC patients. Our study demonstrates a possible mechanism for the development of cSCC involving AhR-mediated signaling by epidermal keratinocytes and recruitment of Th17 cells.

This study was undertaken with the aim to compare the T stages in a series of cutaneous squamous cell carcinoma (cSCC) patients using both the eighth edition of the Union for International Cancer Control (UICC) TNM Classification of Malignant Tumours (TNM8) and Brigham and Women's Hospital (BWH) staging systems. This would allow comparison of the two to determine suitability with regards to T stage and the effect on local recurrence and nodal disease. This was a six-year retrospective cohort study of patients with primary invasive cSCC of the head and neck who were diagnosed and treated at Western Sussex Hospitals Trust in the United Kingdom between 2007 and 2012. The TNM8 and BWH staging systems were applied to these primary cSCCs. A total of 695 invasive cSCCs treated in 604 patients over six years were identified. Most patients were male (76%), with a mean (range) age of 81 (50-103) years. The most common location for local recurrence was the scalp (n = 26, 58%). Regional metastasis occurred most commonly in the parotid gland (n = 20, 63%). All tumours were classified using both staging systems. Specifically, 432 tumours remained in the same T stage (61%), and 192 were downstaged (27%) and 71 upstaged using the BWH (10%). The median (SD) follow-up time was 23 (28) months (range 1-123). The BWH alternative staging system overlapped with the TNM8 in high-stage and low-stage tumour assignment. The highest percentage of local recurrence and regional metastasis occurred in T2b tumours. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-17A is a key proinflammatory cytokine indicated in multiple pathologies, including skin tumorigenesis. While IL-17A is a signature cytokine of Th17 cells, IL-17A is also produced by other cell types, including type 3 innate lymphoid cells (ILC3s) in the skin, particularly in patients with psoriasis. Interestingly, we detect CD45+Lin−(CD3−CD14−CD19−CD20−) IL-17A+ cells in the cutaneous squamous cell carcinomas (cSCCs) by flow cytometry of the cell suspensions prepared from tumor tissues. Consistently, we found CD3−IL-17+ cells in tumor tissue of skin cSCCs by immunohistochemistry staining of serial sections of SCCs from both immunocompetent and immunocompromised patients (e.g., transplant patients on iatrogenic long-term immunosuppressive therapy). In several immunocompromised patients, the CD3−IL-17+ cells consist of over 90% of the total IL-17+ cells in the tumor tissue. Furthermore, these CD3−IL-17+ cells are negatively stained for SMA, CD11b, and CD19, suggesting that they are unlikely to be fibroblast, myeloid cells, or B cells. Taken together, we found a population of lineage-negative IL-17A-producing cells present in the cSCCs, which share the "CD45+Lin−" features with ILCs. This study suggests that IL-17A can be produced by immune cell populations other than T cells in skin SCCs. [ABSTRACT FROM AUTHOR]

Efficient drugs are needed for countering the worldwide high incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis. Indirubin derivatives represent promising candidates, but their effects in cSCC cells have not been reported before. Here, we investigated the efficacy of three indirubin derivatives (DKP-071, -073 and -184) in four cSCC cell lines. High efficacy was seen in SCL-I, SCL-II, SCC-12 and SCC-13, resulting in up to 80% loss of cell proliferation, 60% loss of cell viability and 30% induced apoptosis (10 µM). Apoptosis was further enhanced in combinations with TNF-related apoptosis-inducing ligand (TRAIL). Induction of reactive oxygen species (ROS) appeared as critical for these effects. Thus, antioxidative pretreatment completely abolished apoptosis as well as restored cell proliferation and viability. Concerning the pathways, complete activation of caspases cascades (caspases-3, -4, -6, -7, -8 and -9), loss of mitochondrial membrane potential, activation of proapoptotic PKCδ (protein kinase C delta), inhibition of STAT3 (signal transducer and activator of transcription 3), downregulation of antiapoptotic XIAP (X-linked inhibitor of apoptosis protein) and survivin as well as upregulation of the proapoptotic Bcl-2 protein Puma and the cell cycle inhibitor p21 were obtained. Importantly, all activation steps were prevented by antioxidants, thus proving ROS as a master regulator of indirubins’ antitumor effects. ROS induction presently develops as an important issue in anticancer therapy.

Although the number of cutaneous squamous cell carcinoma (cSCC) cases is increasing, the effectiveness of systemic therapy for the treatment of advanced cSCC is limited. Since cSCC possesses a high tumor mutation burden (TMB) compared to other cancer species, and since high TMB correlated with increased neoantigens and the efficacy of anti‐PD1 antibodies (Abs) in various cancers, cSCC could be a target for anti‐PD1 Abs monotherapy. In this report, we describe a case of unresectable recurrent cSCC of the scalp with meningeal invasion, but highly expressed programmed death‐ligand 1 (PD‐L1), treated with nivolumab monotherapy. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer among Caucasians in the United States, with rising incidence over the past decade. Treatment for non-melanoma skin cancer, including cSCC, in the United States was estimated to cost $4.8 billion in 2014. Thus, an understanding of cSCC pathogenesis could have important public health implications. Immune function impacts cSCC risk, given that cSCC incidence rates are substantially higher in patients with compromised immune systems. We report a systematic review of published associations between cSCC risk and the human leukocyte antigen (HLA) system. This review includes studies that analyze germline class I and class II HLA allelic variation as well as HLA cell-surface protein expression levels associated with cSCC risk. We propose biological mechanisms for these HLA-cSCC associations based on known mechanisms of HLA involvement in other diseases. The review suggests that immunity regulates the development of cSCC and that HLA-cSCC associations differ between immunocompetent and immunosuppressed patients. This difference may reflect the presence of viral co-factors that affect tumorigenesis in immunosuppressed patients. Finally, we highlight limitations in the literature on HLA-cSCC associations, and suggest directions for future research aimed at understanding, preventing and treating cSCC. [ABSTRACT FROM AUTHOR]

Summary: Aim: To identify the risk of developing metastases to regional nodes in patients with cutaneous squamous cell carcinomas (CSCCs) of the head and neck. Methods: A retrospective study of patients with CSCC treated with surgical excision alone between 2000 and 2002 was performed. Demographic details of the patients, the site, size, differentiation, depth of invasion, clearance of surgical margins, and the presence of perineural or lymphovascular invasion of the lesion were documented. During the follow up period, patients with regional metastases were identified. The site of the metastasis and the time after the primary resection were documented and statistical analysis was performed using Chi-square and logistic regression analysis. Results: One hundered and ninety-four patients were included and 218 CSCCs were excised in total during the period of 3 years. The scalp was the most common site of skin lesion, followed by the ear. The incidence of regional metastatic disease was found to be 5.15%. The parotid gland was the most common area of regional metastasis. No metastases occurred after the first 2 years of follow up. The pinna, the poor differentiation and incomplete excision margins were found to be associated with regional metastasis independently, with odds ratio of 16, 21, and 2 respectively. Conclusions: The rate of regional metastasis from CSCC remains low. The parotid gland was the most favoured metastatic site. Patients with poorly differentiated squamous cell carcinoma (SCC) located on the ear and incomplete excision margins were at the greatest risk for developing regional lymph node metastasis and require close follow up. [Copyright &y& Elsevier]

Background.Among patients with cutaneous squamous cell carcinoma (SCC) of the head and neck, recent studies have shown that those with involvement of the parotid gland also have a high incidence of neck node involvement. Treatment of the neck by either surgery or radiotherapy is therefore recommended among patients with parotid SCC, even if clinical examination is negative. The aim of this study was first to analyze patterns of metastatic spread in the parotid and cervical lymph nodes and then to correlate the pattern of involved nodes with the primary cutaneous site in order to guide the appropriate extent of surgery, should neck dissection be used to treat the neck in patients with parotid SCC. Methods.A cohort of 209 patients with cutaneous SCC of the head and neck and clinically evident regional metastatic disease was reviewed retrospectively from 3 Australian institutions. The distribution of involved nodes was obtained from pathology reports; the anatomic sites of primary cutaneous cancers were then correlated with these findings. Results.Among 209 patients, 171 (82%) had clinical parotid involvement. Of these, 28 had clinical neck disease, whereas 143 had parotid disease alone. Thirty-eight (18%) patients had neck disease only. A total of 199 patients were treated surgically, whereas 10 received radiotherapy alone. Surgery included 172 parotidectomies and 151 neck dissections (93 of which were elective). Primary sites were cheek (21.7%), pinna (20.4%), temple (15.8%), forehead (15.8%), postauricular region (5.9%), neck (5.3%), anterior scalp (5.3%), posterior scalp (3.3%), periorbital (3.3%), nose (2.6%), and chin (0.6%). Among pathologically positive necks, level II was most frequently involved (79%). Level IV (13%) and level V (17%) were only involved in extensive lymph node disease, the exception being for isolated level V metastases from the posterior scalp. Conclusions.Primary sites were mainly localized to the lateral aspect of the head. Among patients with cutaneous SCC involving the parotid and neck, level II was the most commonly involved neck level. The distribution of involved nodes suggests that in a patient with parotid involvement and a clinically negative neck with an anterolateral primary, a supraomohyoid neck dissection, always including the external jugular lymph node(s) would be appropriate. In the case of a posterior primary, level V should be dissected as well. In patients with parotid SCC and a clinically positive neck, a comprehensive neck dissection is recommended. © 2006 Wiley Periodicals, Inc. Head Neck, 2006 [ABSTRACT FROM AUTHOR]

Efficient drugs are needed for countering the worldwide high incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis. Indirubin derivatives represent promising candidates, but their effects in cSCC cells have not been reported before. Here, we investigated the efficacy of three indirubin derivatives (DKP-071, -073 and -184) in four cSCC cell lines. High efficacy was seen in SCL-I, SCL-II, SCC-12 and SCC-13, resulting in up to 80% loss of cell proliferation, 60% loss of cell viability and 30% induced apoptosis (10 µM). Apoptosis was further enhanced in combinations with TNF-related apoptosis-inducing ligand (TRAIL). Induction of reactive oxygen species (ROS) appeared as critical for these effects. Thus, antioxidative pretreatment completely abolished apoptosis as well as restored cell proliferation and viability. Concerning the pathways, complete activation of caspases cascades (caspases-3, -4, -6, -7, -8 and -9), loss of mitochondrial membrane potential, activation of proapoptotic PKCδ (protein kinase C delta), inhibition of STAT3 (signal transducer and activator of transcription 3), downregulation of antiapoptotic XIAP (X-linked inhibitor of apoptosis protein) and survivin as well as upregulation of the proapoptotic Bcl-2 protein Puma and the cell cycle inhibitor p21 were obtained. Importantly, all activation steps were prevented by antioxidants, thus proving ROS as a master regulator of indirubins' antitumor effects. ROS induction presently develops as an important issue in anticancer therapy. [ABSTRACT FROM AUTHOR]

Aryl hydrocarbon receptor (AhR) provides a deeper insight into the pathogenesis of cutaneous squamous cell carcinoma (cSCC). AhR ligands, such as 6-formylindolo[3,2-b] carbazole (FICZ), and 7,12-Dimethylbenz[a]anthracene (DMBA), constitute major substrates for the cytochrome P450 (CYP) family, and influence the expression of various cytokine genes, including IL-17 and IL-23 -related genes via the AhR. On the other hand, proinflammatory cytokines could drive tumor progression through the TRAF-ERK5 signaling pathway in cSCC. From the above findings, we hypothesized that AhR ligands might enhance the mRNA expression of proinflammatory cytokines via the AhR, leading to the development of cSCC. The purpose of this study was to investigate (1) the immunomodulatory effects of FICZ and DMBA on normal human keratinocytes (NHKCs), focusing on IL-17, and related cytokines/chemokines (IL-23, IL-36γ, and CCL20), (2) the expression of these factors in AhR-dependent pathways using a two-stage chemically induced skin carcinogenesis mouse model, and (3) the expression of these factors in lesion-affected skin in cSCC. Both FICZ and DMBA augmented the expression of CYP1A1, p19, CCL20, and IL-36γ mRNA in NHKCs in vitro . Moreover, the mRNA expression of these proinflammatory factors, as well as IL-17, in mouse cSCC is significantly decreased in the AhR-(fl/fl) Krt5-(Cre) mice compared to wild type mice, leading to a decrease in the number of developed cSCC lesions. Furthermore, CCL20, IL-23, as well as IL-17, are detected in the lesion-affected skin of cSCC patients. Our study demonstrates a possible mechanism for the development of cSCC involving AhR-mediated signaling by epidermal keratinocytes and recruitment of Th17 cells., (Copyright © 2020 Sato, Fujimura, Hidaka, Lyu, Tanita, Matsushita, Yamamoto and Aiba.)