Cases Of cSCC Research Articles

Low-coverage whole genome sequencing of FFPE-derived-DNA and extracellular vesicle-associated DNA in patients with metastatic cancer.

e14523 Background: Low-coverage whole genome sequencing (LC-WGS) of tumors provides valuable insight into molecular changes driving oncogenesis. A novel liquid biopsy source of tumor DNA for analysis is from extracellular vesicles (EV) obtained from blood. This study compared copy number alteration (CNA) profiles generated from LC-WGS of Formalin-Fixed Paraffin-Embedded (FFPE) DNA and EV-associated DNA in cancer patients. Methods: Three metastatic base of tongue (BOT), two of which were Human Papillomavirus-related (HPV+) and two metastatic cutaneous squamous cell carcinoma (cSCC) patients were included. EV were isolated using ultracentrifugation from patients’ plasma. DNA was extracted from FFPE tumor tissue and EV. LC-WGS aiming for 0.5-1X coverage was performed using a validated method. CNA profiles were generated using the QDNAseq package, with gains defined as a log2 ratio ≥0.15 and losses < -0.15. Results: CNA profiles of FFPE samples from BOT patients demonstrated significant variation regardless of HPV status, with a mean of 20 regions containing 125 CNA (amplifications or deletions) per sample. The cSCC FFPE samples demonstrated a mean of 23 regions containing 189 CNA per sample. Overall, EV-associated DNA CNA profiles had limited similarity with primary FFPE. EV-associated DNA showed a lower number of CNA regions and CNA, with a mean of 3.7 CNA regions and 11.4 CNA for BOT samples and 6.5 regions and 15.9 CNA for cSCC samples. The HPV-BOT sample showed 2/3 EV-CNA regions matched corresponding FFPE-CNA profile (n = 15). The two HPV+ samples were less consistent with only 1/3 and 1/5 EV-CNA regions matching FFPE-CNA profiles (n = 39 and n = 6, respectively). The two cSCC cases showed more consistency with 4/6 and 6/7 EV-CNA regions matching FFPE-CNA profiles (n = 21 and n = 25, respectively). In the matched CNA regions, the mean CNA in EV-associated DNA was 7.5 and in FFPE-DNA was 97. Conclusions: Although selected EV-associated DNA CNA regions reflected the primary tumors, these were limited in number and did not globally reflect the FFPE derived CNA profiles.

Discontinuing voriconazole induced no completely regression of multiple cutaneous squamous cell carcinoma in a hematopoietic stem cell transplant patient

Voriconazole is a universal anti-fungal prophylaxis, which is frequently taken to the patients after hematopoietic stem cell transplantation and solid organ transplantation. Voriconazole can cause phototoxicity, multiple erythema in sun-exposed areas may develop actinic keratosis and cutaneous squamous cell carcinoma (cSCC) while taking voriconazole. In North America and Europe, case reports of phototoxicity and aggressive cSCC in patients on voriconazole have been documented. Also 4 cases of voriconazole-associated cSCC have recently been reported in Japan. We describe a Japanese woman with multiple cSCC associated with recurrence of cSCC after discontinuing voriconazole.

A comparative study of the frequency of myofibroblasts and macrophages between the oral and cutaneous squamous cell carcinoma.

Background. Oral squamous cell carcinoma (OSCC) is among the ten most frequent malignant tumors, with SCC accounting for 94% of oral malignancies. Myofibroblasts and macrophages are multifunctional cells that have a crucial role in the biological behavior of these tumors. This study aimed to comparatively evaluate the frequency of myofibroblasts and macrophages between oral and cutaneous squamous cell carcinomas. Methods. Sixty paraffin blocks, consisting of 20 cases of OSCC, 20 cases of CSCC, 10 cases of normal skin, and 10 cases of normal oral mucosa, were selected for this descriptive-analytical cross-sectional study. To evaluate the prevalence of myofibroblasts, α-SMA staining and CD163 markers for macrophages were used. In this study, the data were analyzed with Wilk-Shapiro test and t-test using SPSS 19. Statistical significance was set at P<0.05. Results. The mean myofibroblast scores in CSCC and OSCC were 20.05 and 20.95, respectively, with no significant difference between the means (P>0.05). The mean macrophage scores in the skin and oral cavity were 28.125 and 49.67, respectively, with a statistically significant difference (P<0.05), indicating that the mean oral macrophage score was significantly higher than that in the skin. There was no significant difference between the presence and accumulation of macrophages and myofibroblasts between the oral and cutaneous SCCs; however, the intensity of accumulation and color pattern in OSCC and CSCC were higher than those in the normal skin and mucosa (P<0.05). Conclusion. According to the results of this study, it appears the biological behavior of OSCC and CSCC does not depend on myofibroblasts, and other factors might be involved.

Association between PD-L1 expression and lymph node metastasis in cutaneous squamous cell carcinoma.

To clarify the relationship between programmed cell death ligand 1 (PD-L1) expression in cutaneous squamous cell carcinoma (cSCC) and clinicopathological variables. We examined PD-L1 expression in tumor cells (TCs) and tumor infiltrating immune cells (ICs) in 46 cases of cSCC by immunohistochemistry. In each case, we employed two methods-intensity and proportion scores-to evaluate PD-L1 expression in TCs. For the evaluation of PD-L1 expression in ICs, only the proportion score was used. Association between PD-L1 expression and clinicopathological variables was analyzed using Fisher's exact test. High intensity scores in TCs were observed in 18 of the 46 cases (39.1%) and low intensity scores were observed in 28 cases (60.9%). Applying the proportions, using cut-off values of ≥1% and 50%, positive scores in TCs were observed in 36 (78.3%) and 20 cases (43.5%), respectively. PD-L1-positive ICs were observed in 29 (63%) and seven cases (15.2%), using cut-off values of ≥1% and 10%, respectively. The high intensity scores in TCs correlated with lymph node metastasis (P=0.008) and female gender (P=0.017), although positive proportions in TCs or ICs were not significantly related to lymph node metastasis. A multivariate analysis showed that high intensity of PD-L1 expression in TCs was an independent risk factor for lymph node metastasis. The results suggested that high intensity of PD-L1 expression in TCs is associated with lymph node metastasis in cSCC.

Gene expression imputation identifies candidate genes and susceptibility loci associated with cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer with genetic susceptibility loci identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) using imputed gene expression levels can identify additional gene-level associations. Here we impute gene expression levels in 6891 cSCC cases and 54,566 controls in the Kaiser Permanente Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort and 25,558 self-reported cSCC cases and 673,788 controls from 23andMe. In a discovery-validation study, we identify 19 loci containing 33 genes whose imputed expression levels are associated with cSCC at false discovery rate < 10% in the GERA cohort and validate 15 of these candidate genes at Bonferroni significance in the 23andMe dataset, including eight genes in five novel susceptibility loci and seven genes in four previously associated loci. These results suggest genetic mechanisms contributing to cSCC risk and illustrate advantages and disadvantages of TWAS as a supplement to traditional GWAS analyses.

Activation and overexpression of the aryl hydrocarbon receptor contribute to cutaneous squamous cell carcinomas: an immunohistochemical study

BackgroundIn vitro studies showed that the aryl hydrocarbon receptor (AHR) contributed to the development of cutaneous squamous cell carcinomas, but supporting clinical data are lacking.MethodsImmunohistochemical analysis was used to detect the expression of AHR, CYP1A1, EGFR, and Ki-67 in 10 actinic keratosis (AK) cases, 10 Bowen disease (BD) cases, 20 cutaneous squamous cell carcinoma (cSCC) cases and 20 normal skin samples. H-scores were used to assess the immunoreactivity.ResultsWeak positive AHR immunoreactivity was found in all normal skin samples, while strong positive AHR immunoreactivity was found in atypical squamous proliferation (AK, BD and cSCC) cases. H-scores and the rate of strong immunostaining of the atypical squamous proliferation cases were higher than those of normal controls (p < 0.01). Nuclear expression of AHR was higher in atypical squamous proliferation cases than in normal controls (p < 0.01). H-scores and the nuclear expression rate of AHR were significantly higher in AK and BD cases than cSCC cases (p < 0.01). CYP1A1 expression was low and showed no differences among the four studied groups (p > 0.05). The H-score of AHR was positively correlated with EGFR expression (r = 0.54, p < 0.01) in atypical squamous proliferation cases but was not correlated with CYP1A1 (r = − 0.17, p = 0.295) and Ki-67 (r = − 0.48, p = 0.222) expression.ConclusionAHR plays a vital role in cSCC pathogenesis. The overexpression and activation of AHR are involved in the early development of skin cancers. AHR expression correlates with EGFR expression and may influence cell proliferation. AHR is a valuable therapeutic target for skin cancers.

Common Mitochondrial Haplogroups and Cutaneous Squamous Cell Carcinoma Risk.

Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in United States, and its incidence is substantially higher in men than women, but the reasons for the difference are unknown. We explored whether common mitochondrial DNA (mtDNA) haplogroups, which have been associated with cancer risk, and in particular squamous cell carcinoma risk arising in other organs, could explain this biological sex difference in cSCC susceptibility.Methods: We performed a retrospective cohort study using data from the Genetic Epidemiology Research in Adult Health and Aging cohort composed of 67,868 non-Hispanic white subjects (7,701 cSCC cases and 60,167 controls). Genotype information on >665,000 SNPs was generated using Affymetrix Axiom arrays designed to maximize genome-wide coverage, and 102 high-quality mtDNA SNPs were used to determine mtDNA haplogroups. Associations between each mtDNA haplogroup and cSCC risk were evaluated by logistic regression analysis adjusting for age, sex, and population stratification using ancestry principal components.Results: cSCC was more common in men (15.4% vs. 8.4% for women). Nine common mtDNA haplogroups (frequency ≥1%) were identified in addition to the most common haplogroup, H, used as the reference group. No association with cSCC risk was detected for any of the mtDNA haplogroups or overall or sex-stratified analyses.Conclusions: Common mitochondrial variation is not associated with cSCC risk.Impact: This well-powered study refutes the hypothesis that common mitochondrial haplogroups play a role in the differential sex predilection of cSCCs. Cancer Epidemiol Biomarkers Prev; 27(7); 838-41. ©2018 AACR.

Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma.

The immune system has been implicated in the pathophysiology of cutaneous squamous cell carcinoma (cSCC) as evidenced by the substantially increased risk of cSCC in immunosuppressed individuals. Associations between cSCC risk and single nucleotide polymorphisms (SNPs) in the HLA region have been identified by genome-wide association studies (GWAS). The translation of the associated HLA SNPs to structural amino acids changes in HLA molecules has not been previously elucidated. Using data from a GWAS that included 7238 cSCC cases and 56,961 controls of non-Hispanic white ancestry, we imputed classical alleles and corresponding amino acid changes in HLA genes. Logistic regression models were used to examine associations between cSCC risk and genotyped or imputed SNPs, classical HLA alleles, and amino acid changes. Among the genotyped SNPs, cSCC risk was associated with rs28535317 (OR = 1.20, p = 9.88 × 10- 11) corresponding to an amino-acid change from phenylalanine to leucine at codon 26 of HLA-DRB1 (OR = 1.17, p = 2.48 × 10- 10). An additional independent association was observed for a threonine to isoleucine change at codon 107 of HLA-DQA1 (OR = 1.14, p = 2.34 × 10- 9). Among the classical HLA alleles, cSCC was associated with DRB1*01 (OR = 1.18, p = 5.86 × 10- 10). Conditional analyses revealed additional independent cSCC associations with DQA1*05:01 and DQA1*05:05. Extended haplotype analysis was used to complement the imputed haplotypes, which identified three extended haplotypes in the HLA-DR and HLA-DQ regions. Associations with specific HLA-DR and -DQ alleles are likely to explain previously observed GWAS signals in the HLA region associated with cSCC risk.

PD-L1, B7-H3, and PD-1 expression in immunocompetent vs. immunosuppressed patients with cutaneous squamous cell carcinoma.

To characterize the expression of co-signaling molecules PD-L1, PD-1, and B7-H3 in cutaneous squamous cell carcinoma (cSCC) by immune status. We retrospectively analyzed 66 cases of cSCC treated with surgical resection from 2012 to 2015. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 (Tum-PD-L1%), B7-H3 (Tum-B7-H3%), density of peri and intratumoral CD8 T cells (CD8 density), proportion of CD8 T cells expressing PD-1 (CD8-PD-1%) and of tumor-infiltrating immune cells (TII) expressing PD-L1 (TII-PD-L1%). Of 66 cases, 42 were immunocompetent, 24 immunosuppressed (13 organ transplant, 8 HIV+, 3 other). Defining positive expression at > 5%, 26% of tumors were positive for PD-L1, 85% for B7-H3, 80% had CD8 T cells that expressed PD-1 and 55% had TII that expressed PD-L1. Tum-B7-H3% was significantly higher (median 60 vs. 28%, p = 0.025) in immunocompetent vs. immunosuppressed patients, including when factoring in cause of immunosuppression. No significant difference in Tum-PD-L1%, TII-PD-L1%, CD8 density, or CD8-PD-1% was observed. Tumors from HIV+ patients lacked PD-L1 expression, and had lower B7-H3% (median 2.5 vs. 60%, p = 0.007), and higher CD8 density (median 75% vs. 40%, p = 0.04) compared to immunocompetent patients. Higher tumor grade (Rs = 0.34, p = 0.006) and LVI (Rs = 0.61, p < 0.001) were both associated with higher Tum-PD-L1%. cSCC showed expression of PD-L1 on tumor in 26% of cases, and high tumor B7-H3 expression (85%) and PD-1 expression on CD8 TILs (80%). Tumor B7-H3 expression was significantly higher in immunocompetent vs. immunosuppressed patients, largely driven by very low expression in HIV+ patients.

Accuracy of death certification in cutaneous squamous cell carcinoma: A retrospective case review

Accuracy of death certification in cutaneous squamous cell carcinoma: A retrospective case review

Alcohol intake and risk of nonmelanoma skin cancer: a systematic review and dose-response meta-analysis.

Nonmelanoma skin cancer (NMSC) comprises mainly basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). The association between alcohol intake and NMSC has been inconclusive; therefore the objective of this study is to quantify the relationship between alcohol intake and NMSC using meta-analyses. A systematic literature search of PubMed and Embase was performed on 30 October 2016. Eligible articles were case-control or cohort studies that examined alcohol intake and risk of BCC or cSCC and reported relative risks (RRs) with 95% confidence intervals (CIs). Of the 307 articles identified, 13 case-control and cohort studies were included in the systematic review, including 95 241 NMSC cases (91 942 BCC and 3299 cSCC cases). A random-effects model was used to obtain summary RRs and 95% CIs for dose-response meta-analyses. For every 10-gram increase in ethanol intake per day, a positive association was found for both BCC (summary RR of 1·07; 95% CI 1·04-1·09) and cSCC (summary RR of 1·11; 95% CI 1·06-1·16). While there was evidence suggesting a nonlinear association for BCC, it may be due to the sparse data at higher alcohol intake levels. This meta-analysis found evidence that alcohol drinking is positively associated with both BCC and cSCC risk in a dose-dependent manner. These results should be interpreted with caution due to potential residual confounding. Nonetheless, because alcohol drinking is a prevalent and modifiable behaviour, it could serve as an important public health target to reduce the global health burden of NMSC.

Low incidence of metastasis and recurrence from cutaneous squamous cell carcinoma found in a UK population: Do we need to adjust our thinking on this rare but potentially fatal event?

Cutaneous squamous cell carcinoma (cSCC) is the commonest skin cancer with metastatic potential, however, reported rates of metastasis varies greatly. All cases of primary cSCC on the Isle of Wight between 2005 and 2014 were identified and retrospectively followed for recurrence and/or metastasis. Primary outcome was to identify the rate of metastasis/recurrence from cSCC. Secondary outcomes included associated risk factors for metastasis/recurrence, death from cSCC, and time from diagnosis of primary cSCC to event. A total of 1122 patients with 1495 tumors were identified within the study period. A total of 18 metastasized and 40 recurred, an overall incidence of 1.2% and 2.7%, respectively. Eight patients died from their disease. Risk of metastasis from cSCC in the UK general population is likely to be in the order of 1.2%. Where metastasis occurs this is often within 2 years. Recurrence rates are higher following curette and cautery. If treated adequately both recurrence and metastasis from cSCC is a rare event. Not all cSCC cases need follow-up instead time should be spent educating patients around signs of recurrence/metastasis then discharged, relieving burden on secondary care. Multi-disciplinary teaming meetings are expensive and should be limited to complex cases.

Cisplatin and Cetuximab Treatment for Metastatic Cutaneous Squamous Cell Carcinoma: A Systematic Review.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and metastasizes in 2% to 5% of cases. Systematic evaluation of published cases of metastatic cSCC (mSCC) treated with cisplatin or cetuximab from 1989 to 2014. A literature search was performed to identify cases of mSCC treated with cisplatin or cetuximab. Patient demographics, tumor characteristics, response rates, and disease-free survivals were extracted. A total of 60 cases of mSCC treated with cisplatin and 9 cases treated with cetuximab reported in the literature from 1989 to 2014 were included in the analysis. Patients treated with cetuximab obtained a complete response of 67%, an overall response of 78%, and a median disease-free survival of 25 (range 3-48) months. Patients treated with cisplatin obtained a complete response of 22%, an overall response of 45%, and a median disease-free survival of 14.6 (range 3-112) months. Head-to-head prospective clinical studies between cetuximab and cisplatin are needed to determine which is more efficacious. In addition, prospective tumor registries and randomized controlled trials should be developed in order to establish the ideal systemic regimen in cSCC.

Sun protection for preventing basal cell and squamous cell skin cancers.

'Keratinocyte cancer' is now the preferred term for the most commonly identified skin cancers basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which were previously commonly categorised as non-melanoma skin cancers (NMSC). Keratinocyte cancer (KC) represents about 95% of malignant skin tumours. Lifestyle changes have led to increased exposure to the sun, which has, in turn, led to a significant increase of new cases of KC, with a worldwide annual incidence of between 3% and 8%. The successful use of preventive measures could mean a significant reduction in the resources used by health systems, compared with the high cost of the treatment of these conditions. At present, there is no information about the quality of the evidence for the use of these sun protection strategies with an assessment of their benefits and risks. To assess the effects of sun protection strategies (i.e. sunscreen and barrier methods) for preventing keratinocyte cancer (that is, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) of the skin) in the general population. We searched the following databases up to May 2016: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trial registries and the bibliographies of included studies for further references to relevant trials. We included randomised controlled clinical trials (RCTs) of preventive strategies for keratinocyte cancer, such as physical barriers and sunscreens, in the general population (children and adults), which may provide information about benefits and adverse events related to the use of solar protection measures. We did not include trials focused on educational strategies to prevent KC or preventive strategies in high-risk groups. Our prespecified primary outcomes were BCC or cSCC confirmed clinically or by histopathology at any follow-up and adverse events. Two review authors independently selected studies for eligibility using Early Review Organizing Software (EROS). Similarly, two review authors independently used predesigned data collection forms to extract information from the original study reports about the participants, methods of randomisation, blinding, comparisons of interest, number of participants originally randomised by arm, follow-up losses, and outcomes, and they assessed the risk of bias. We resolved any disagreement by consulting a third author and contacted trial investigators of identified trials to obtain additional information. We used standard methodological procedures expected by Cochrane. We included one RCT (factorial design) that randomised 1621 participants.This study compared the daily application of sunscreen compared with discretionary use of sunscreen, with or without beta-carotene administration, in the general population. The study was undertaken in Australia; 55.2% of participants had fair skin, and they were monitored for 4.5 years for new cases of BCC or cSCC assessed by histopathology. We found this study to be at low risk of bias for domains such as allocation, blinding, and incomplete outcome data. However, we found multiple unclear risks related to other biases, including an unclear assessment of possible interactions between the effects of the different interventions evaluated (that is, sunscreen and beta-carotene). We found no difference in terms of the number of participants developing BCC (n = 1621; risk ratio (RR) 1.03, 95% confidence interval (CI) 0.74 to 1.43) or cSCC (n = 1621; RR 0.88, 95% CI 0.50 to 1.54) when comparing daily application of sunscreen with discretionary use, even when analyses were restricted to groups without beta-carotene supplementation. This evidence was of low quality, which means that there is some certainty that future studies may alter our confidence in this evidence.We reported adverse events in a narrative way and included skin irritation or contact allergy.We identified no studies that evaluated other sun protection measures, such as the use of sun-protective clothing, sunglasses, or hats, or seeking the shade when outdoors. In this review, we assessed the effect of solar protection in preventing the occurrence of new cases of keratinocyte cancer. We only found one study that was suitable for inclusion. This was a study of sunscreens, so we were unable to assess any other forms of sun protection. The study addressed our prespecified primary outcomes, but not most of our secondary outcomes. We were unable to demonstrate from the available evidence whether sunscreen was effective for the prevention of basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC).Our certainty in the evidence was low because there was a lack of histopathological confirmation of BCC or cSCC in a significant percentage of cases. Amongst other sources of bias, it was not clear whether the study authors had assessed any interaction effects between the sunscreen and beta-carotene interventions. We think that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Occupation and relative risk of cutaneous squamous cell carcinoma (cSCC): A 45-year follow-up study in 4 Nordic countries

The age-adjusted incidence of cutaneous squamous cell carcinoma (cSCC) in the Nordic countries has increased during the last 60years, and the identification of occupational variation in the relative risk of cSCC may have preventive implications. We sought to describe variation in the relative risk of cSCC between occupational categories in Finland, Iceland, Norway, and Sweden. This is a historical prospective cohort study based on record linkages between census data for 12.9 million people and cancer registry data from 1961 to 2005. Standardized incidence ratios for cSCC were estimated for 53 occupational categories with the cSCC incidence rates for the national population of each country used as reference. During follow-up, 87,619 incident cases of cSCC were reported to the national cancer registries. In all countries combined, significant increased standardized incidence ratios were observed among seamen, military personnel, public safety workers, technical workers, teachers, transport workers, physicians, dentists, nurses, other health workers, religious workers, clerical workers, administrators, and sale agents (standardized incidence ratios between 1.08 and 1.77). Information on occupation was based on 1 point in time only. The occupational variation of the relative risk of cSCC might be associated with socioeconomic factors, and to some extent to occupational exposures.

Non-melanoma skin cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper provides consensus recommendations on the management of cutaneous basal cell carcinoma and squamous cell carcinoma in the head and neck region on the basis of current evidence. Recommendations • Royal College of Pathologists minimum datasets for NMSC should be adhered to in order to improve patient care and help work-force planning in pathology departments. (G) • Tumour depth is of critical importance in identifying high-risk cutaneous squamous cell carcinoma (cSCC), and should be reported in all cases. (R) • Appropriate imaging to determine the extent of primary NMSC is indicated when peri-neural involvement or bony invasion is suspected. (R) • In the clinically N0 neck, radiological imaging is not beneficial, and a policy of watchful waiting and patient education can be adopted. (R) • Patients with high-risk NMSC should be treated by members of a skin cancer multidisciplinary team (MDT) in secondary care. (G) • Non-infiltrative basal cell carcinoma (BCC) <2 cm in size should be excised with a margin of 4-5 mm. Smaller margins (2-3 mm) may be taken in sites where reconstructive options are limited, when reconstruction should be delayed. (R) • Where there is a high risk of recurrence, delayed reconstruction or Mohs micrographic surgery should be used. (R) • Surgical excision of low-risk cSCC with a margin of 4 mm or greater is the treatment of choice. (R) • High-risk cSCC should be excised with a margin of 6 mm or greater. (R). • Mohs micrographic surgery has a role in some high-risk cSCC cases following MDT discussion. (R) • Delayed reconstruction should be used in high-risk cSCC. (G) • Intra-operative conventional frozen section in cSCC is not recommended. (G) • Radiotherapy (RT) is an effective therapy for primary BCC and cSCC. (R) • Re-excision should be carried out for incompletely excised high-risk BCC or where there is deep margin involvement. (R) • Incompletely excised high-risk cSCC should be re-excised. (R) • Further surgery should involve confirmed marginal clearance before reconstruction. (R) • P+ N0 disease: Resection should include involved parotid tissue, combined with levels I-III neck dissection, to include the external jugular node. (R) • P+ N+ disease: Resection should include level V if that level is clinically or radiologically involved. (R) • Adjuvant RT should include level V if not dissected. (R) • P0 N+ disease: Anterior neck disease should be managed with levels I-IV neck dissection to include the external jugular node. (R) • P0 N+ posterior echelon nodal disease (i.e. occipital or post-auricular) should undergo dissection of levels II-V, with sparing of level I. (R) • Consider treatment of the ipsilateral parotid if the primary site is the anterior scalp, temple or forehead. (R) • All patients should receive education in self-examination and skin cancer prevention measures. (G) • Patients who have had a single completely excised BCC or low-risk cSCC can be discharged after a single post-operative visit. (G) • Patients with an excised high-risk cSCC should be reviewed three to six monthly for two years, with further annual review depending upon clinical risk. (G) • Those with recurrent or multiple BCCs should be offered annual review. (G).

Expression of HIF-2α and VEGF in Cervical Squamous Cell Carcinoma and Its Clinical Significance.

CSCC is a systemic disease involving polygenic alteration and multiple steps, and HIF and VEGF are closely associated with tumorigenesis. Specimens surgically resected from 64 cases of CSCC and 22 cases of normal cervical tissue were selected randomly to detect the expression of HIF-2α and VEGF in CSCC for exploring their clinical significance; information regarding the age, lymph node metastasis, and FIGO staging were collected as well; expression of HIF-2α and VEGF was detected by qPCR and immunohistochemistry. We found that the expression of HIF-2α and VEGF mRNA in CSCC was significantly higher than that of normal cervical tissues and showed a positive correlation between them. The positive rates of HIF-2α and VEGF protein expression in CSCC and normal cervical tissues were 93.8% and 18.2%, respectively, with correlation between them. The expression of both HIF-2α and VEGF mRNA did not relate closely to age but the FIGO staging and lymph node metastasis. Compared with the counterpart control group, CSCC tissues with high FIGO staging and lymph node metastasis had a higher level of HIF-2α and VEGF mRNA expression. So, HIF-2α and VEGF were overexpressed in CSCC, which has a great clinical significance for its diagnosis.

Clinical and Genetic Factors Associated with Cutaneous Squamous Cell Carcinoma in Kidney and Heart Transplant Recipients.

Cutaneous squamous cell carcinoma (cSCC) occurs with higher frequency and recurrence rates, increased morbidity and mortality, and more aggressive metastasis in kidney and heart transplant recipients compared to the general population but all transplant recipients do not develop cSCC. In addition, the phenotypic expression of cSCC among transplant recipients can vary between mild disease to extensive recurrent metastatic disease. These clinically observed differences in occurrence and severity of cSCC among transplant recipients suggest the possibility that an underlying genetic component might modify risk. We identified 88 white post-transplant cSCC cases (71 kidney and 17 heart) and 300 white post-transplant controls (265 kidney and 35 heart) using a DNA biobank linked with de-identified electronic medical records. Logistic regression was used to determine adjusted odds ratios (OR) for clinical characteristics and single nucleotide polymorphisms (SNP) associated with cSCC in both a candidate SNP and genome wide analysis. Age (OR 1.08 [1.05-1.11], p<0.001) and azathioprine exposure (OR 8.64 [3.92-19.03], p<0.001) were significantly associated while gender, smoking tobacco use, dialysis duration and immunosuppression duration were not. Ten candidate SNPs previously associated with non-melanoma skin cancer in the general population were significantly associated with cSCC in transplant recipients. Genome wide association analysis implicated SNPs in genes previously associated with malignancy, CSMD1 (OR 3.14 [1.90-5.20]) and CACNA1D (OR 2.67 [1.73-4.10]). This study shows an association of increasing age and azathioprine exposure with cSCC and confirms a genetic contribution for cSCC development in kidney and heart transplant recipients.

Mutational landscape of aggressive cutaneous squamous cell carcinoma.

Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias. Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion. The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.

Do Beta-Human Papilloma Viruses Cause Cutaneous Squamous Cell Carcinoma in Immunocompetent Individuals?

Background: Existing epidemiological evidence is controversial regarding the possible association between Beta Human papillomavirus (B-HPV) and cutaneous squamous cell carcinoma (cSCC) in immunocompetent individuals. Objectives: Perform a systematic review of cohort and case-control studies that assessed B-HPV and the risk of cSCC in immunocompetent individuals to assess the current data. Materials and methods: We performed a systematic literature search for studies in humans through March 17, 2014, with no specified start date or language restrictions and employed predefined search criteria. The included studies complied with the predefined inclusion and exclusion criteria and were agreed upon by both authors after review of abstracts and full text. Data extraction included general study information comprising latitude of study location, study design, the number of cases and controls, method of HPV detection and the number of types of HPV detected. Furthermore, study results were designated as the general and/or type specific B-HPV adjusted Odds Ratio or Relative Risk. Results: This is the largest review to be conducted on this topic in healthy individuals. We evaluated 4,056 cSCC cases and 7,067 controls that were collected from 16 casecontrol and 4 cohort studies included in this review. Studies were subdivided into six categories depending on the method of HPV detection used. Among the 20 studies, 18 (90%) showed a significant association between B-HPV and cSCC. More specifically, HPV8 and HPV38 were most commonly reported to have a significant association with cSCC. Conclusion: This systematic review provides further evidence supporting the role of B-HPV in the development of cSCC in healthy individuals and supports a possible type-specific HPV 8, 38 involvements in cSCC. Our findings highlight the need for large multi-center prospective research to validate these associations.