Solar keratoses and their relationship to non-melanoma skin cancers

Solar keratoses belong to the list of clinically invisible dermatoses, as the loss of their horny layer may create the illusion that they have disappeared, and numerous subclinical lesions can be highlighted by 5-fluorouracil therapy. Solar keratoses are recognized as potential precursors for squamous cell carcinoma. However, basal cell carcinoma (BCC) may develop in a soft type of solar keratoses as a consequence of migration of pluripotential adnexal epithelial cells in reparative response to trauma, particularly in areas rich in adnexal structures, such as the face. These intraepithelial resident adnexal cells may result in the development of BCC following chronic solar exposure and damage.     

Dermoscopy in the diagnosis and management of non-melanoma skin cancers

Over the past two decades, dermoscopy has remarkably enhanced the diagnostic accuracy of pigmented skin lesions and, more recently, of non-pigmented skin disorders, including skin cancers, inflammatory and infectious diseases. With respect to non-melanoma skin cancers (NMSC), dermoscopy is an effective diagnostic tool for the clinical assessment of basal cell carcinoma, Bowen's disease, actinic keratosis and squamous cell carcinoma. Besides its relevance for diagnostic purposes, further applications of dermoscopy in the management of NMSC have been suggested in the preoperative evaluation, in monitoring the outcome of topical, light-based or laser treatments and in the post-treatment follow-up. This article summarizes the dermoscopic diagnostic criteria of NMSC and provides a review of the published literature as well as of our own experience on the usefulness of dermoscopy in monitoring surgical and medical treatment of NMSC.     

Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients

A prospective, open randomized crossover trial was conducted to evaluate the efficacy of acitretin for chemoprevention of squamous cell carcinomas and basal cell carcinomas in renal allograft recipients. Analysis was performed according to the intention-to treat principle. Twenty-three patients with previous history of non-melanoma skin cancer enrolled into the study and were randomly allocated into two groups. They crossed over at the end of 1 year. Eleven (47.8%) patients completed the 2-year trial. Twelve (52.2%) patients withdrew from the trial. Nine of these withdrew because of side-effects of acitretin. The majority of the patients who continued with the acitretin could tolerate 25 mg of acitretin daily or on alternate days. The number of squamous cell carcinomas (SCC) observed in patients while on acitretin was significantly lower than that in the drug-free period (P = 0.002). A similar trend was observed in patients with basal cell carcinomas, but this was not significant and the numbers were small. Side-effects were a major limiting factor. A severe rebound increase in SCC occurred in one patient after the acitretin was ceased.     

Risk of multiple primary cancers following melanoma and non-melanoma skin cancer

Background The relationship between cutaneous malignancies and successive primary cancers has been studied since several years, but it still remains controversial. Objective The aim of this study was to evaluate the excess risk of multiple primary cancer among the population of Umbria, Italy, that survived a skin cancer. Methods The data registered in the Umbrian Population Cancer Registry from 1994 to 2006 were collected, recorded, and analysed in accordance to the standard methods recommended for cancer registries. Among skin cancer patients, those with multiple cutaneous and non-cutaneous cancers were selected. Only sites with a frequency of more than five cases were considered. The expected number of cases was obtained from indirect standardization with regional incidence rates in several sites that incurred in the overall period. The significance of the observed/expected ratios and the corresponding 95% CI were based on the Poisson distribution. Results In men, a significant standardized incidence ratio (SIR) was found for melanoma (2.21), non-melanoma skin cancers (1.86), Hodgkin's (4.95) and non-Hodgkin lymphoma (1.82), and tongue/mouth cancer (2.47). In women, melanoma, non-melanoma skin and breast cancer showed a significant high SIRs (4.13, 1.55 and 1.28 respectively). All other cancers showed a non-significant SIR. Considering all sites combined and all sites except skin cancers, the analysis showed a significant excess in men, whereas a significant risk was observed in women only when also skin cancers were considered. Conclusions Data from the whole of Umbrian population revealed that skin cancer patients experience marked excess risk of further primary cancers. The main risk in both genders is skin melanoma and other skin cancers. The excess of lymphomas and tongue/mouth cancers is also significant in men, and breast cancer in women. These observations prompt us to include a screening for these cancers in the follow-up of our patients surviving a skin malignancy.     

树突细胞在某些皮肤病中的作用

树突细胞是一类专职的抗原提呈细胞,它们有不同的亚群.在免疫反应中,树突细胞能从微生物及细胞周边环境中接受信号从而启动和调节免疫反应.树突细胞表面表达不同的微生物受体,细胞因子受体和表面分子.其功能状态决定了是激发免疫反应还是诱导免疫耐受.因此,异常功能状态的树突细胞可引发不同的皮肤疾病,如自身免疫性疾病和癌症.反之,树突细胞也可被开发研制成疫苗用于治疗这些疾病.

Abstract：

Dendritic cells (DCs), a subset of professional antigen-presenting cells, are classified into different subtypes. DCs can initiate and regulate immune responses after receiving signals from microbes and extracellular environment. They express different microbial receptors, cytokine receptors and surface molecules. The functional status of DCs determines whether they trigger immune response or induce immunotolerance. Hence, DCs with abnormal function can result in different skin diseases, including autoimmune diseases and cancers. Conversely, DCs can also be exploited for the development of vaccines to treat these diseases.     

Evaluation of the treatment of non-melanoma skin cancers by surgical excision

A retrospective study of all non-melanoma skin cancers excised by two dermatologists at a private practice in 2004 (excluding Mohs microscopic surgery cases) was conducted. Two hundred and forty-one patients were treated, with a total of 453 tumours excised. The overall incomplete excision rate was 2.2% (10/453). For basal cell cancers, the incomplete excision rate was 1.54% (5/324) and for squamous cell cancers including Bowen's disease the incomplete excision rate was 3.9% (5/129). The majority of repairs were primary closures (82.6%). Although a significant proportion of the tumours were from the head and neck region (45.9%), this study demonstrated that careful patient selection, experience of the surgeon and adherence to recommended excision margins can achieve a favourable incomplete excision rate.     

Human papillomavirus-DNA loads in actinic keratoses exceed those in non-melanoma skin cancers

Recent studies suggest a role of cutaneous human papillomaviruses (HPV) in non-melanoma skin cancer (NMSC) development. In this study viral DNA loads of six frequent HPV types were determined by quantitative, type-specific real-time-PCR (Q-PCR) in actinic keratoses (AK, n=26), NMSC (n=31), perilesional tissue (n=22), and metastases of squamous cell carcinomas (SCC) (n=8) which were previously shown to be positive for HPV5, 8, 15, 20, 24, or 36. HPV-DNA loads in AK, (partially microdissected) NMSC, and perilesional skin ranged between one HPV-DNA copy per 0.02 and 14,200 cell equivalents (median: 1 HPV-DNA copy per 344 cell equivalents; n=48). In 32 of the 79 HPV-positive skin biopsies and in seven of the eight metastases viral loads were even below the detection limit of Q-PCR. Low viral loads in NMSC were confirmed by in situ-hybridization showing only a few HPV-DNA-positive nuclei per section. Viral loads in SCC, basal cell carcinomas, and perilesional tissue were similar. But, viral loads found in AK were significantly higher than in SCC (p=0.035). Our data suggest that persistence of HPV is not necessary for the maintenance of the malignant phenotype of individual NMSC cells. Although a passenger state cannot be excluded, the data are compatible with a carcinogenic role of HPV in early steps of tumor development.     

非黑素瘤皮肤癌患者生活质量及影响因素调查

【摘要】 目的 调查非黑素瘤皮肤癌（NMSC）患者生活质量及其影响因素。方法 2017年6月至2020年1月,通过自制问卷及皮肤病生活质量指数量表（DLQI）调查153例在中国医学科学院皮肤病医院整形外科住院接受手术治疗的NMSC患者的人口学、临床、行为学资料,并计算DLQI评分评估其生活质量。采用χ2检验、Kruskal-Wallis H检验、多因素Logistic回归分析NMSC患者生活质量的影响因素。结果 回收有效问卷146份（95.4%）。146例患者年龄31～92岁,101例（69.2%）60岁以上,59例（40.4%）有长期紫外线暴露史。基底细胞癌（BCC）66例（45.2%）,侵袭性鳞状细胞癌（SCC）57例（39.0%）,乳房外Paget病16例（11.0%）及Bowen病7例（4.8%）。DLQI评分中位数［M（P25,P75）］为3（1,7）,99例（67.8%）生活质量受到影响,52例（35.6%）受到轻度影响,47例（32.2%）受到中度以上影响。多因素Logistic回归分析显示,皮肤癌类型、长期紫外线照射史、3个及以上子女数量影响患者的生活质量。结论 NMSC降低患者的生活质量,且皮肤癌类型、长期紫外线照射史、子女数量是NMSC患者生活质量的影响因素。     

Differential expression of E prostanoid receptors in murine and human non-melanoma skin cancer

Enhanced prostaglandin production via upregulated cyclooxygenase-2 (COX-2) expression is a likely contributing factor in ultraviolet B (UVB)-induced non-melanoma skin cancer (NMSC), which consists primarily of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). The four E prostanoid (EP) receptors, designated EP1 through EP4, are known to bind prostaglandin E2 (PGE2), the major prostaglandin present in the skin. We used murine models of UVB-induced SCC and BCC, as well as human NMSC from sun-exposed sites, to investigate the expression of EP receptors during UVB-induced tumorigenesis. We observed that UVB-induced murine SCC are associated with markedly altered expression patterns of the EP receptors when compared with non-irradiated skin. In contrast, expression of all EP receptors was largely absent in UVB-induced murine BCC. We also observed expression of all four EP receptors in human SCC, with altered expression of their mRNA levels as compared with adjacent tumor-free skin. Consistent with our murine studies, no EP receptor expression was detected in human BCC, and their mRNA expression levels showed no change from the adjacent non-tumor-bearing skin. These data suggest that altered EP receptor expression may play a differential role in the development of UVB-induced SCC and BCC in murine and human skin.     

Risk of second cancers after the diagnosis of non-melanoma skin cancer in Korean patients

Individuals with a personal history of non-melanoma skin cancer (NMSC) are known to have an increased risk of subsequent cancers. However, most of the studies regarding this fact were done on Caucasian populations. We investigated whether Korean patients with NMSC have an increased risk of developing second cancers compared to the general Korean population. Five hundred and thirty-two patients diagnosed with NMSC at the Department of Dermatology of Yonsei University Health System from 1999 to 2008 were assessed for development of second cancers. The overall second cancer incidence was increased among patients diagnosed with NMSC compared with the general population in Korea: 37 second cancer total (standardized incidence ratio [SIR] 1.38, 95% confidence interval [CI] 1.10-1.90); 23 second cancers in males (SIR 4.24, 95% CI 2.69-6.36); and 14 second cancers in females (SIR 2.28, 95% CI 1.25-3.83). There were significantly increased incidence ratios for NMSC (eight second cancers [SIR 9.52, 95% CI 4.11-18.77]), bladder cancer (four second cancers [SIR 4.21, 95% CI 1.15-10.78]) and nasopharyngeal cancer (one second cancer [SIR 20.00, 95% CI: 1.51-25.33]). Korean patients diagnosed with NMSC had more second cancers, particularly other skin cancers. This study provides additional evidence that NMSC may be a clinically significant and substantial risk factor for second cancers even in a Korean population, in which the incidence of NMSC is much lower than Caucasians.     

Expression of the apoptosis-suppressing protein Bcl-2 in non-melanoma skin cancer

Basal cell carcinoma (BCC) is typically a slow-growing malignant tumour, composed of cells similar to those in the basal area of the epidermis. We investigated the expression of bcl-2 (B-cell leukaemia/lymphoma-2) in BCC, and also in squamous cell carcinoma (SCC) of the skin. The proto-oncogene bcl-2 encodes a protein which inhibits programmed cell death (apoptosis). The protein is expressed in basal cells in normal human epithelium, but not in the suprabasal cell layers. Immunohistochemical localization using a monoclonal anti-Bcl-2 antibody revealed bcl-2 expression in all the BCCs (15 patients). SCCs did not express bcl-2 (five patients). The positive Bcl-2 staining of BCC tumour cells supports the hypothesis that BCCs originate from the basal layer of the epidermis. The bcl-2 expression of BCC tumour cells also suggests a neoplastic transformation caused by extended cell survival rather than increased cell proliferation. This type of neoplastic growth is possibly associated with less aggressive tumour behaviour.     

A broad spectrum of human papillomavirus types is present in the skin of Australian patients with non-melanoma skin cancers and solar keratosis

BACKGROUND: Human papillomavirus (HPV) may play a role in the pathogenesis of non-melanoma skin cancer (NMSC) in epidermodysplasia verruciformis (EV) patients, but in the general population no specific HPV types have been associated with these lesions. Objectives To examine the spectrum of HPV types present in the skin and tumours of Australian patients with NMSC or solar keratosis (SK). METHODS: Biopsies from tumours, and cotton swab samples of perilesional skin and buttock skin from each of 59 Australian patients with basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or SK were tested for HPV DNA by polymerase chain reaction (PCR) using HPV consensus (FAP) primers and by type-specific primers for HPV 38 and candidate HPV 92. The identification of HPV type from consensus PCR was performed by sequencing and comparison with GenBank. RESULTS: In total, 49 of 59 (83%) patients harboured HPV DNA, which was detected in 28 of 64 (44%) biopsies, 48 of 64 (75%; P < 0.001) perilesional swabs and 36 of 59 (61%; P = 0.04) buttock swabs. Forty-five different HPV types/putative types were detected: 15 were previously characterized HPV types, 17 were earlier described putative types and 13 were new putative types. In addition, six subtypes and four variants of HPV sequences were identified. HPV types within the B1 group (EV HPV types) were found in 26 of 64 (40%) lesions, 44 of 64 (69%) perilesional swabs and 35 of 59 (59%) buttock swabs. HPV 38 was detected in 23 of 59 (39%) patients, and was found in seven of 16 (43%) SKs, but was less common in SCCs [three of 23 (13%); P = 0.037] and BCCs [four of 25 (16%); P = 0.056]. Candidate HPV 92 was found in seven of 59 (12%) patients. CONCLUSIONS: A broad spectrum of HPV types, the majority from the B1 group, was found in skin of Australian patients with skin tumours. HPV 38 was found significantly more often in SK than in SCC. However, the role of cutaneous HPV infection in the pathogenesis of NMSC remains elusive.     

Prevention of non-melanoma skin cancers with nicotinamide in transplant recipients: a case-control study

Background

Nicotinamide is the precursor of nicotinamide adenine dinucleotide (NAD+), an essential cofactor for adenosine triphosphate (ATP) production. It has recently been reported to be effective in reducing the rates of new non-melanoma skin cancers (NMSCs) and actinic keratosis (AKs).

Objectives

We studied the efficacy of oral nicotinamide as treatment for AKs in transplant recipients.

Materials & methods

We recruited 38 transplant (eight liver and 30 kidney) patients with single or multiple AKs. Nineteen patients were randomly assigned to Group 1 and took nicotinamide 500 mg/daily (cases); the other 19 patients were randomly assigned to Group 2 without nicotinamide (controls). At base-line, AKs were identified, measured, and photographed for follow-up. Five patients underwent an AK biopsy for histopathology. Statistical analyses were performed using the Student t test.

Results

At baseline, no statistically significant differences were observed regarding AK size between the two groups. After six months, among the cases, AKs had significantly decreased in size in 18/19 patients (88%). Among these 18 patients, seven patients (42%) had shown complete clinical regression and no patient developed new AKs. Conversely, among the controls, 91% showed an increase in AK size and/or developed new AKs. Seven pre-existing AKs progressed to squamous-cell carcinoma.

Conclusion

Nicotinamide appears to be effective in preventing and treating AKs, although the mechanisms are still unclear. Further studies with a larger sample of organ transplant recipients and a longer follow-up period are needed to further support our conclusions.

     

Machine-learning classification of non-melanoma skin cancers from image features obtained by optical coherence tomography

Background/purpose: A number of publications have suggested that optical coherence tomography (OCT) has the potential for non-invasive diagnosis of skin cancer. Currently, individual diagnostic features do not appear sufficiently discriminatory. The combined use of several features may however be useful.
Methods: OCT is based on infrared light, photonics and fibre optics. The system used has an axial resolution of 10 μm, lateral 20 μm. We investigated the combined use of several OCT features from basal cell carcinomas (BCC) and actinic keratosis (AK). We studied BCC (41) and AK (37) lesions in 34 consecutive patients. The diagnostic accuracy of the combined features was assessed using a machine-learning tool.
Results: OCT images of normal skin typically exhibit a layered structure, not present in the lesions imaged. BCCs showed dark globules corresponding to basaloid islands and AKs showed white dots and streaks corresponding to hyperkeratosis. Differences in OCT morphology were not sufficient to differentiate BCC from AK by the naked eye. Machine-learning analysis suggests that when a multiplicity of features is used, correct classification accuracies of 73% (AK) and 81% (BCC) are achieved.
Conclusion: The data extracted from individual OCT scans included both quantitative and qualitative measures, and at the current level of resolution, these single factors appear insufficient for diagnosis. Our approach suggests that it may be possible to extract diagnostic data from the overall architecture of the OCT images with a reasonable diagnostic accuracy when used in combination.     

Expression of dihydrodiol dehydrogenase plays important roles in apoptosis- and drug-resistance of A431 squamous cell carcinoma

BACKGROUND: Dihydrodiol dehydrogenase (DDH) is a member of the aldo-keto reductases superfamily which may be involved in normal detoxification process of environmental mutagenic hazards like polycyclic aromatic hydrocarbons (PAH). Previous clinical studies have demonstrated the over-expression of DDH in various types of cancers, including cutaneous squamous cell carcinoma (SCC), and its correlation with tumor progression and grave prognosis. OBJECTIVE: To investigate possible mechanisms for DDH's correlation with tumor progression and unfavorable prognosis. METHODS: DDH expression in SCC A431 cell line was examined by quantitative real-time PCR and immunoblotting. RNA interference (RNAi) by transduction with retroviral vector containing DDH-targeting small interfering RNA was employed to inhibit DDH expression by A431 cells. With DDH expression inhibited or not, sensitivity of A431 cells to UVB-induced apoptosis and cytotoxicity of chemotherapeutic agent bleomycin were then examined and compared. RESULTS: DDH was found highly expressed by SCC A431 cells, which was barely detectable in other normal or malignant cutaneous cells, including keratinocytes, fibroblast, and basal cell carcinoma cell line. RNAi Inhibition of DDH expression in A431 cells led to increased sensitivity to UVB-induced apoptosis and cytotoxicity of bleomycin treatment. CONCLUSION: DDH may play important roles in tumor progression of SCC via induction of apoptosis- and drug-resistance.     

Hyperthermia induces endoplasmic reticulum-mediated apoptosis in melanoma and non-melanoma skin cancer cells

Hyperthermia has been revived as a promising approach for cancer treatment. To understand the underlying mechanisms of hyperthermic killing of cancer cells, we examined the cytotoxic effects of hyperthermia on various skin cancer cell lines using cell viability, morphological analyses, and caspase activation assays. Hyperthermia induced cytotoxicity in a time- and temperature-dependent manner. At middle dose/time combinations, heat-induced apoptosis, whereas at higher doses, necrosis was the mechanism of cell death. To investigate the mechanisms of hyperthermia-induced apoptosis, we examined the activation of extrinsic (Caspase 8) and intrinsic (Caspase 9) apoptotic pathways. Hyperthermia did not activate Caspases 8 or 9, but did activate Caspase 3/7, suggesting a non-conventional apoptotic pathway. Last, analysis of Grp78 expression and Caspase 12 or 4 activation indicated that hyperthermia induced endoplasmic reticulum-mediated apoptosis. Thus, hyperthermia induced apoptosis in two types of skin cancer cells through endoplasmic reticulum-mediated apoptosis and not through the classical intrinsic or extrinsic apoptosis pathways. Hyperthermia may be a promising treatment for basal cell carcinoma and melanoma, bypassing the antiapoptotic defenses concentrated in the intrinsic and extrinsic apoptosis pathways. These results also raise the possibility that heat may be combined with other approaches for induction of apoptosis to achieve synergistic killing of skin cancers.     

Registration of non-melanoma skin cancers in Scotland—how accurate are site and morphology codes?

Although underreporting; of nun-melanoma skin cancers to cancer registries is widely acknowledged, less is known about the accuracy of information held about registered cases. In 1993, the accuracy of a random sample of cancer registrations in Scotland attributed to the year 1(W() was assessed by reference to relevant medical records. The sample contained 290 registrations of non-melanoma skin cancers, 251 (90%) of which had records available for scrutiny. Here we report the results of a detailed analysis of the accuracy of site and morphologv coding of non-melanoma skin cancers. Following reabstraction of details from available medical records, only three cases (1.2%) did not retain the same first three digit ICD-9 site code (173. —), although a further three cases were judged to have been registered in error. There were 56 (21.5%) discrepancies in morphology coding, but 21 of these arose through inferences about morphology in the absence of microscopic confirmation, and most of the remainder were of a relatively minor nature. In summary, it does seem possible to collect data about non-melanoma skin cancers to a reasonably high standard of accuracy. This provides some justification to those who advocate an increased effort directed towards improving levels of completeness of ease ascertainment.