Dysembryogenetic Pathogenesis of Basal Cell Carcinoma: The Evidence to Date.

The Basal Cell Carcinoma (BCC) is a sort of unique tumour due to its combined peculiar histological features and clinical behaviour, such as the constant binary involvement of the epithelium and the stroma, the virtual absence of metastases and the predilection of specific anatomical sites for both onset and spread. A potential correlation between the onset of BCC and a dysembryogenetic process has long been hypothesised. A selective investigation of PubMed-indexed publications supporting this theory retrieved 64 selected articles published between 1901 and 2024. From our analysis of the literature review, five main research domains on the dysembryogenetic pathogenesis of BCC were identified: (1) The correlation between the topographic distribution of BCC and the macroscopic embryology, (2) the correlation between BCC and the microscopic embryology, (3) the genetic BCC, (4) the correlation between BCC and the hair follicle and (5) the correlation between BCC and the molecular embryology with a specific focus on the Hedgehog signalling pathway. A large amount of data from microscopic and molecular research consistently supports the hypothesis of a dysembryogenetic pathogenesis of BCC. Such evidence is promoting advances in the clinical management of this disease, with innovative targeted molecular therapies on an immune modulating basis being developed.

Evaluation of the incidence of melanoma and non-melanoma skin cancer in patients with systemic lupus erythematosus and systemic sclerosis.

BACKGROUND: The incidence of skin cancer in patients with systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) has only been investigated with retrospective studies enrolling a low number of patients. The aims of our study were to assess the incidence of skin cancer in two large cohorts of patients, one with SLE and the other with SSc and investigating possible risk factors. METHODS: Ninety SLE, 53 SSc patients and 392 control subjects were enrolled. A questionnaire including personal and medical details was fulfilled. The severity of photoaging, photosensitivity and sun exposure habits was assessed. Skin lesions were evaluated using a video-dermatoscope. Suspicious lesions were surgically removed. RESULTS: The incidence of skin cancer was not different to those of controls. However, a decrease in the incidence of basal cell carcinoma was found in patients with SLE. This finding associated negatively with photosensitivity. SSc patients with skin malignancies did not report photosensitivity and did not adopt a careful photoprotection. A positive association was found between skin cancer and diffuse cutaneous sclerosis, pitting scars, severe photoaging and treatment with Iloprost. CONCLUSIONS: Regular avoidance of sun exposure and photoprotection are effective in reducing the development of skin cancer in patients with autoimmune diseases.

High-Risk Non-Melanoma Skin Cancers: Biological and Therapeutic Advances.

Nonmelanoma skin cancers (NMSCs) are the most common cancers, with high-risk NMSCs sharing features such as poor histologic differentiation, invasion into deeper layers, and anatomic location. NMSC includes basal cell carcinoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma. Herein, the authors describe advances in understanding the genetic mechanisms of malignant transformation and the composition of tumor microenvironment for these cancers. They summarize recent therapeutic advances, including targeted therapy and immunotherapy for NMSCs. Effective skin protection against ultraviolet radiation-induced carcinogenesis remains an urgent unmet need for NMSC prevention. The authors highlight immune-based interventions as novel strategies to address this need.

Carcinogenic risk in patients treated with UVA-1 phototherapy: A 5-year retrospective study.

BACKGROUND: UVA-1 phototherapy was first used to treat atopic dermatitis and afterwards to several other skin diseases. The contribution of UVA-1 in human photocarcinogenesis, skin photoaging, immune suppression, and hyperpigmentation is now well established. The actual contribution of UVA-1 radiation to the development of malignant melanoma (MM) in humans cannot be excluded. PURPOSE: The aim of the study is to evaluate the risk of developing skin cancers (non-melanoma skin cancers (NMSCs) and MM) in patients treated with UVA-1 phototherapy with a 5-year dermatological follow-up. METHODS: We conducted a retrospective cohort study with 31 patients with morphea and atopic dermatitis treated with medium dose UVA-1 phototherapy (34 J/cm2). All enrolled patients underwent an oncologic prevention visit annually with a 5-year follow-up with clinical evaluation of the entire skin surface. RESULTS: During the 5-year follow-up, we recorded a case of basal cell carcinoma (BCC) in the cervical region and one case of MM on the back (pT1a). In both cases, the patients were female and affected by morphea. The Glogau 3 group is prevalent (42%), which is consistent with moderate to severe aging; the data appear to be compatible with the age. CONCLUSIONS: This study attests that medium-dose UVA-1 phototherapy does not increase the risk of developing skin tumors and that UVA-1 phototherapy is not a worsening factor of facial photoaging. The main limitation of the study is the small sample size, avoiding to obtain statistically significant values. It was not possible to analyze individually the actual daily sun exposure during the 5-year observation period and to correlate it in terms of time and tumor development. Further studies with large sample sizes will be needed to confirm our data. Our study reaffirms how the dermatological examination performed annually is essential in the follow-up of patients undergoing this type of therapy.

Common skin cancers and their association with other non-cutaneous primary malignancies: a review of the literature.

It has long been recognized that a history of skin cancer puts one at risk for additional primary skin cancers. However, more variable data exists for the risk of developing a non-cutaneous primary cancer following a diagnosis of skin cancer. The data are most variable for Basal Cell Carcinoma (BCC), the most common and least aggressive type of skin cancer. While early studies imply that BCC does not impart a larger risk of other primary non-cutaneous cancers, more recent studies with larger populations suggest otherwise. The cancers most significantly associated with BCC are lip, oropharyngeal, and salivary gland cancer. There is also burgeoning evidence to suggest a link between BCC and prostate, breast, and colorectal cancer, but more data are needed to draw a concrete conclusion. Squamous Cell Carcinoma (SCC), the second most common type of skin cancer, has a slightly more defined risk to other non-cutaneous primary malignancies. There is a notable link between SCC and non-Hodgkin's lymphoma (NHL), possibly due to immunosuppression. There is also an increased risk of other cancers derived from squamous epithelium following SCC, including oropharyngeal, lip, and salivary gland cancer. Some studies also suggest an increased risk of respiratory tract cancer following SCC, possibly due to shared risk factors. Melanoma, a more severe type of skin cancer, shows a well-defined risk of additional primary non-cutaneous malignancies. The most significant of these risks include NHL, thyroid cancer, prostate cancer, and breast cancer along with a host of other cancers. Each of these three main skin cancer types has a profile of genetic mutations that have also been linked to non-cutaneous malignancies. In this review, we discuss a selection of these genes to highlight the complex interplay between different tumorigenesis processes.

A prospective cohort study exploring the joint influence of sunlight exposure and tanning bed use on basal cell carcinoma, squamous cell carcinoma, and melanoma risk.

Exposure to solar ultraviolet (UV) radiation and use of UV-emitting tanning devices are known risk factors for skin cancer. Few studies have explored the interaction between these risk factors, namely how the risk of skin cancer increases among those who both have been exposed to high levels of natural sunlight and regularly use tanning beds. Nurses' Health Study II followed 116,430 women, aged 25-42, from 1991 to 2011. Cumulative average UV exposure was based on participants' residences at follow-up periods. History of severe sunburn during ages 15-20 was used as a proxy for early-life sunlight exposure. Tanning bed use in early life data was collected. Participants reported melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) diagnoses. We built multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of skin cancer associated with joint effects of sunlight exposure and tanning bed use. Participants with high sunlight exposure and tanning bed use during high school/college had an increased risk of BCC (HR = 1.53, 95% CI 1.37-1.71, Pinteraction=0.01; vs. low sun exposure and no tanning bed use). Participants with a history of severe sunburns and tanning bed use during high school/college were at increased risk of BCC (HR = 1.62, 95% CI 1.47-1.79, Pinteraction=0.02; vs. no sunburns and no tanning bed use). No significant interactions were found between sunlight exposure and tanning bed use on SCC and melanoma risk. We found significant interactions between sunlight exposure and tanning bed use on the risk of BCC.

Efficacy of photodynamic therapy using ALAHCl in gel with a lipid nanoemulsion and MALHCl in cream in superficial basal cell carcinoma.

INTRODUCTION AND OBJECTIVE: Photodynamic therapy (PDT) is a therapeutic option for low-risk basal cell carcinoma (BCC). The aim of the study was to assess the efficacy of topical PDT in the treatment of superficial BCC (sBCC) using two different photosensitizers: aminolevulinic acid hydrochloride (ALA-HCl) in a gel formulation with a lipid nanoemulsion (ALA-HCl in gel) and ALA methyl ester hydrochloride (MAL-HCl) in a cream formulation (MAL-HCl in cream). MATERIAL AND METHODS: 21 patients were treated twice with a one week interval between treatments. The formulations were applied onto lesions: 10 patients were treated with MAL-HCl in cream, and 11 with ALA-HCl in gel. After three hours of incubation and removing the preparations, fluorescence was assessed. The skin areas were then irradiated with red light 630 ± 5 nm. RESULTS: At the follow-up visit 12 weeks after the second treatment, complete clinical remission was found in 82% after ALA-HCl in gel and in 80% after MAL-HCl in cream. An excellent cosmetic result was found in 96% of patients after MALHCl in cream and in 100% after ALA-HCl in gel. Faster skin healing and less post-inflammatory hyperpigmentation during follow-up visits was observed after treatment with ALA-HCl in gel. CONCLUSIONS: Both formulations - ALA-HCl in gel and MAL-HCl in cream - were highly effective photosensitisers for PDT. The advantage of ALA-HCl in a gel formulation with a lipid nanoemulsion was faster skin healing, resulting in better cosmetic results.

Skin cancer in renal transplant recipients: outcomes from a safety net hospital in Boston.

BACKGROUND: Renal transplant recipients (RTRs) are prone to skin cancer due to the immunosuppression required to maintain graft function. Existing studies of skin cancer in RTRs focus on patients with Fitzpatrick skin types I-II, with limited documentation of incidence in skin types III-VI. This study seeks to better characterize skin cancers in RTRs with skin types III-VI. PRIMARY AIMS: Compare the incidence of skin cancer in RTRs of skin types I-II with skin types III-VI. SECONDARY AIMS: Explore the association between the development of skin cancer and other contributing factors in RTRs of skin types I-VI. METHODS: Retrospective chart review of RTRs at a single institution between January 1, 2000 and December 31, 2022. Patients were followed from the date of transplant to the last clinical follow-up or death. 777 RTRs were included in the study, including 245 patients with Fitzpatrick skin types I-II and 532 with skin types III-VI. A total of 48 patients developed NMSCs, 2 patients developed melanoma, and 3 patients developed Kaposi sarcoma. RESULTS AND CONCLUSIONS: There is a higher incidence of skin cancer in RTRs with Fitzpatrick skin types III-VI compared to the reported incidence among non-transplant recipients of the same skin types, but the incidence remains considerably lower compared to RTR of skin types I-II.

[Chinese guildeline on diagnosis and treatment of basal cell carcinoma (2023 edition)].

Basal cell carcinoma (BCC) is the most common skin malignancy, with a higher prevalence in Caucasians than in East Asians. Although there is a lack of epidemiological data in China, it is generally believed that the incidence of BCC in China is increasing due to the aging population. A variety of risk factors are related to the occurrence of BCC, among which ultraviolet rays and gene mutations play a major role, especially the abnormal activation of Hedgehog (Hh) signaling pathway, which is considered to be the most important pathogenesis of BCC. The clinical manifestations of BCC are highly specific, and most experienced doctors can make a preliminary diagnosis by clinical manifestations. Dermoscopy and other imaging methods can greatly improve the accuracy of diagnosis, but there are still some atypical or rare types of BCC that need further confirmation through histopathological examination. This guideline is initiated by the National Clinical Research Center for Skin and Immune Diseases (based on Peking University First Hospital). It has invited a panel of experts consisting of 24 senior dermatologists specializing in dermatologic surgery from the Dermatologic Surgery Group of the Chinese Medical Doctor Association of Dermatology, the Dermatologic Surgery Group of the Dermatology & Venereology Committee, Chinese Association of Integration Medicine, and the Dermatologic Surgery and Cosmetic Branch of Clina Leprosy Association. In addition, experts from the Burn and Plastic Surgery (Maxillofacial), Ophthalmology, Otolaryngology, Head and Neck Surgery, Radiation Therapy, and Pathology were also invited to participate. This panel forms the "Chinese Guideline for the Diagnosis and Treatment of Basal Cell Carcinoma" expert group. Based on the latest domestic and international research findings, the guideline was developed through four rounds of discussions by the expert group and revised to provide valuable references for clinical healthcare providers in the diagnosis and treatment of BCC.

Epidemiological and clinical analysis of exposure-related factors in non-melanoma skin cancer: A retrospective cohort study.

BACKGROUND: The incidence of non-melanoma skin cancers (NMSCs) increased over last decades, probably due to environmental concerns or to the increase of frail patients with age related comorbidities. Currently, the relationship of increasing global skin cancer rates with increased ultraviolet radiations (UVRs) resulting from stratospheric ozone depletion, global warming, and air pollution from fossil-fuel combustion. AIMS: We conducted a retrospective epidemiological study including 546 NMSC patients managed at the Dermatology Unit of the Tor Vergata Hospital to highlight different trends of sun exposure or different comorbidities. METHODS: Descriptive and inferential statistical analyses were performed to evidence differences between continous variable and Spearman rank test for dicotomical variables. Charlson Comorbidity Index was calculated to obtain the 10-years survival rate in order to identify the mean comorbidity burden of our patients. RESULTS: Considering patients with comorbidities (73.81%), actinic keratoses (AKs) was the most frequent lesion. In patients with a history of previous melanoma, basal cell carcinoma (BCC) was predominant (ANOVA test, p < 0.05) with a statistically significant correlation (rho = 0.453; p < 0.01). Squamous cell carcinoma (SCC) showed a higher rate in arterial hypertension patients, followed by the chronic heart failure and hematologic neoplasms (60%, 29.7% and 32.1%, respectively) groups. Men were more affected than women, representing 61.54% of patients. Chronic sun exposure is directly correlated with SCC rho = 0.561; p < 0.01), whereas BCC correlated with a history of sunburns (rho = 0.312; p < 0.05). CONCLUSIONS: History of photo-exposition had an important role on NMSC development especially for work or recreational reasons. Sex, age, and presence of comorbidities influenced different NMSC types. BCC was more frequent in younger patients, associated with melanoma and sunburns. The presence of SCC is associated with older patients and the hypertension group. AKs were diagnosed predominantly in oldest men, with a chronic sun-exposure history, and hematologic neoplasms group.

Exposome and basal cell carcinoma: a multicenter case-control study.

BACKGROUND: While ultraviolet radiation (UVR) present in sunlight is recognized as the main etiological agent of skin cancer, the most frequent form of which is basal cell carcinoma (BCC), other exposome factors like pollution, diet, and lifestyle may also contribute. This study aimed to investigate the association of BCC and exposome-related factors in the Spanish population. METHODS: BCC cases (n = 119) and controls (n = 127) with no history of skin cancer were recruited between April 2020 and August 2022 by 13 dermatologists throughout Spain in this prospective multicenter case-control study. RESULTS: The BCC group had a higher proportion of outdoor workers, more years of UVR exposure, and a greater consumption of drugs (statins, ASA, hydrochlorothiazide, ACE inhibitors and omeprazole), P < 0.05. Avoidance of sun exposure was the most used photoprotection measure in both groups. The use of hats or caps was higher in the BCC group (P = 0.01). The solar protection factor (SPF) used 15 years previously was higher in the control group (P = 0.04). The control group had a higher daily screen time (P < 0.001), and practiced more relaxation activities (P = 0.03). Higher linolenic acid intake and lower coffee consumption were the only dietary variables associated with BCC (P < 0.05). Statistical significance for all the aforementioned variables was maintained in the multivariate analysis (P < 0.05). CONCLUSIONS: The study found a significant association between BCC and multiple exposome-related factors in addition to chronic sun exposure in the Spanish population. Primary prevention strategies should target specific populations, such as outdoor workers, promoting sun-safe behaviors and stress-reducing activities, and also adequate skin photoprotection in patients on certain medications associated with increased BCC risk.

Occupational solar exposure and basal cell carcinoma. A review of the epidemiologic literature with meta-analysis focusing on particular methodological aspects.

BACKGROUND: Numerous epidemiologic studies and a few systematic reviews have investigated the association between occupational solar exposure and basal cell carcinoma (BCC). However, previous reviews have several deficits with regard to included and excluded studies/risk estimates and the assessment of risk of selection bias (RoSB). Our aim was to review epidemiologic studies with a focus on these deficits and to use meta-(regression) analyses to summarize risk estimates. METHODS: We systematically searched PubMed (including MEDLINE) and Embase for epidemiologic studies. Study evaluation considered four main aspects of risk of bias assessments, i.e. Selection of subjects (selection bias); Exposure variables; Outcome variables; Data analysis. RESULTS: Of 56 identified references, 32 were used for meta-(regression) analyses. The overall pooled risk estimate for BCC comparing high/present vs. low/absent occupational solar exposure was 1.20 (95% CI 1.02-1.43); among studies without major deficits regarding data analysis, it was 1.10 (95% CI 0.91-1.33). Studies with low and high RoSB had pooled risk estimates of 0.83 (95% CI 0.73-0.93) and 1.95 (95% CI 1.42-2.67), respectively. The definitions of exposure and outcome variables were not correlated with study risk estimates. Studies with low RoSB in populations with the same latitude or lower than Germany had a pooled risk estimate of 1.01 (95% CI 0.88-1.15). CONCLUSION: Due to the different associations between occupational solar exposure and BCC among studies with low and high RoSB, we reason that the current epidemiologic evidence base does not permit the conclusion that regular outdoor workers have an increased risk of BCC.

Incidence and profile of skin cancers in patients following ultraviolet phototherapy without psoralens: A retrospective cohort study.

BACKGROUND: Psoralen + ultraviolet-A (PUVA) is associated with photocarcinogenesis. However, carcinogenic risk with other ultraviolet phototherapies remains unclear. OBJECTIVE: Evaluate whether phototherapy without psoralens increases skin cancer risk. METHODS: Retrospective cohort study of patients treated at a teaching-hospital phototherapy center (1977-2018). Skin cancer records were validated against pathology reports. Age-standardized incidence rates (ASIRs) of skin cancer were evaluated for gender, skin phototype, diagnosis, ultraviolet modality, anatomical site; and compared to provincial population incidence rates (2003). RESULTS: In total, 3506 patients treated with broadband-ultraviolet-B, narrowband-UVB and/or combined UVAB were assessed with a mean follow-up of 7.3 years. Majority of patients had psoriasis (60.9%) or eczema (26.4%). Median number of treatments was 43 (1-3598). Overall, 170 skin cancers (17 melanoma, 33 squamous cell carcinoma and 120 basal cell carcinoma) occurred in 79 patients. Patient-based and tumor-based ASIR of skin cancer was 149 (95% CI: 112-187)/100,000 and 264 (219-309)/100,000 person-years, respectively. There was no significant difference between tumor-based ASIRs for melanoma, squamous cell carcinoma, and basal cell carcinoma compared to the general population; or in phototherapy patients with-psoriasis or eczema; or immunosuppressants. No cumulative dose-response correlation between UVB and skin cancer was seen. LIMITATIONS: Treatment and follow-up duration. CONCLUSION: No increased risk of melanoma and keratinocyte cancer was found with phototherapy.

Basal cell carcinoma arising at the site of a previously irradiated infantile hemangioma.

We describe a case of a previously irradiated infantile hemangioma in a patient 1 year of age. At the age of 78, the patient presented with a pink, pearly plaque at the previously irradiated infantile hemangioma site and was found to have a nodular basal cell carcinoma. [Correction added on 30 August 2023, after first online publication: In the preceding sentence, patient age has been corrected in this version] This case highlights the rare, but long-term risks of radiation therapy for hemangiomas, but also presents an interesting historical vignette in dermatological treatments, with photographic documentation. It also represents the longest time interval between irradiation of an infantile hemangioma and the development of a basal cell skin cancer, 70 years in this case.

Basal Cell Skin Cancer, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Basal cell carcinoma (BCC) is the most common form of skin cancer in the United States. Due to the high frequency, BCC occurrences are not typically recorded, and annual rates of incidence can only be estimated. Current estimated rates are 2 million Americans affected annually, and this continues to rise. Exposure to radiation, from either sunlight or previous medical therapy, is a key player in BCC development. BCC is not as aggressive as other skin cancers because it is less likely to metastasize. However, surgery and radiation are prevalent treatment options, therefore disfigurement and limitation of function are significant considerations. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline an updated risk stratification and treatment options available for BCC.

Genetic variants for smoking behaviour and risk of skin cancer.

Observational studies have suggested that smoking may increase the risk of cutaneous squamous cell carcinoma (cSCC) while decreasing the risks of basal cell carcinoma (BCC), and melanoma. However, it remains possible that confounding by other factors may explain these associations. The aim of this investigation was to use Mendelian randomization (MR) to test whether smoking is associated with skin cancer, independently of other factors. Two-sample MR analyses were conducted to determine the causal effect of smoking measures on skin cancer risk using genome-wide association study (GWAS) summary statistics. We used the inverse-variance-weighted estimator to derive separate risk estimates across genetic instruments for all smoking measures. A genetic predisposition to smoking initiation was associated with lower risks of all skin cancer types, although none of the effect estimates reached statistical significance (OR 95% CI BCC 0.91, 0.82-1.01; cSCC 0.82, 0.66-1.01; melanoma 0.91, 0.82-1.01). Results for other measures were similar to smoking initiation with the exception of smoking intensity which was associated with a significantly reduced risk of melanoma (OR 0.67, 95% CI 0.51-0.89). Our findings support the findings of observational studies linking smoking to lower risks of melanoma and BCC. However, we found no evidence that smoking is associated with an elevated risk of cSCC; indeed, our results are most consistent with a decreased risk, similar to BCC and melanoma.

Non-Invasive Treatment of Basal Cell Carcinoma: Photodynamic Therapy Following Curettage.

BACKGROUND: To investigate the effectiveness, safety, patient satisfaction, and cosmetic outcome of Methyl Aminolevulinate-Photodynamic Therapy (MAL-PDT) following curettage in order to make recommendations for its use in dermatology practices. METHODS: A retrospective chart review of patients who received MAL-PDT following curettage for the indication of basal cell carcinoma (BCC) between 2009 and 2016 at a single private clinic in Ontario, Canada. Two hundred and seventy-eight patients with 352 BCC lesions were included, consisting of 44.2% males (n=123) and 55.8% females (n=155) with a mean age of 57.24 years. The primary outcome measurement consisted of the cure rate. Secondary outcome measurements included side effects, patient satisfaction, and cosmetic outcome, as reported in the medical charts. RESULTS: The overall cure rate was 90.3% (n=318). After controlling for age, sex, and lesion type, nasal lesions were approximately 2.82 (95% CI: 1.24-6.40, P=0.01) times more likely to experience a recurrence. 18.3% of patients (n=51) reported side effects, the most common being burning (n=19). Of those who expressed satisfaction, 100% (n=25) reported being happy. Of lesions with cosmetic data, 90.3% displayed a good response (n=149). CONCLUSION: MAL-PDT following curettage is an effective and safe treatment option for BCC lesions with a good cosmetic outcome and suggested high patient satisfaction. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7133.

A meta-analysis of sunburn and basal cell carcinoma risk.

Basal cell carcinoma (BCC) is the most common cancer in the United States. Sunburn is a modifiable risk factor for BCC. The objective of this project was to synthesize research on BCC and sunburn to quantify the impact and severity of sunburn at different life stages on BCC risk in the general population. A systematic literature search of four electronic databases was conducted and data were extracted by two independent reviewers using standardized forms. Data from 38 studies were pooled using both dichotomous and dose-response meta-analytic methods. BCC risk increased with ever experiencing a sunburn in childhood (OR=1.43, 95% CI: 1.19, 1.72) and with ever experiencing a sunburn in life (OR= 1.40, 95% CI: 1.02, 1.45). Every five sunburns experienced per decade in childhood increased BCC risk by 1.86 (95% CI: 1.73, 2.00) times. Every five sunburns experienced per decade in adulthood increased BCC risk by 2.12 (95% CI: 1.75, 2.57) times and every five sunburns per decade of life increased BCC risk by 1.91 (95% CI: 1.42, 2.58) times. The data on sunburn exposure and BCC show that an increase in number of sunburns at any age increased the risk of BCC. This may inform future prevention efforts.