Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and ...the European Organization of Research and Treatment of Cancer collaborated to develop recommendations on diagnosis and treatment of BCC. A new classification into ‘easy-to-treat (common) BCC and ‘difficult-to-treat’ BCC is proposed. Diagnosis is based on clinicodermatoscopic features for ‘easy-to-treat’ BCCs. Histopathological confirmation is mandatory in ambiguous lesions and in BCCs located in high-risk areas. The first-line treatment of ‘easy-to-treat’ BCC is complete surgery. Microscopically controlled surgery shall be offered for high-risk BCC, recurrent BCC and BCC in critical anatomical sites. Topical therapies (5% imiquimod, 5% fluorouracil) and destructive approaches (curettage, electrocautery, cryotherapy, laser ablation) should be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial BCC and thin nodular BCC. The therapy for a ‘difficult-to-treat’ BCC should preferentially be discussed by a multidisciplinary tumour board. Hedgehog inhibitors, vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCCs. Immunotherapy with anti–programmed cell death 1 (PD-1) antibodies is a promising therapeutic option, currently being investigated in clinical trials. Radiotherapy represents a valid alternative to surgery for BCC on the face, especially in elderly patients. In patients with naevoid basal cell carcinoma syndrome (NBCCS), close surveillance and regular skin examinations are required to diagnose and treat BCCs at early stage. Long-term follow-up is recommended in patients with high-risk BCC subtypes, high-risk sites, multiple BCCs and NBCCS.
•Basal cell carcinoma (BCC) is the most common epithelial malignant tumour in white populations.•A new classification into “easy-to-treat” (common) BCC and “difficult-to-treat” BCC is proposed.•Surgery is the first-line therapy in all types of BCCs.•Treatment choice for advanced BCC should be discussed by a multidisciplinary tumour board.•Hedgehog inhibitors are used in "difficult-to-treat" BCC, and immunotherapy is a promising treatment under investigation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast ...function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.
Molecular diagnostics are increasingly performed routinely in the diagnosis and management of patients with melanoma due to the development of novel therapies that target specific genetic mutations. ...The development of next-generation sequencing (NGS) technologies has enabled to sequence multiple cancer-driving genes in a single assay, with improved sensitivity in mutation detection. The main objective of this study was the design and implementation of a melanoma-specific sequencing panel, and the identification of the spectrum of somatic mutations in a series of primary melanoma samples. A custom panel was designed to cover the coding regions of 35 melanoma-related genes. Panel average coverage was 2,575.5 reads per amplicon, with 92,8% of targeted bases covered ≥500×. Deep coverage enabled sensitive discovery of mutations in as low as 0.5% mutant allele frequency. Eighty-five percent (85/100) of the melanomas had at least one somatic mutation. The most prevalent mutated genes were BRAF (50%;50/199), NRAS (15%;15/100), PREX2 (14%;14/100), GRIN2A (13%;13/100), and ERBB4 (12%;12/100). Turn-around-time and costs for NGS-based analysis was reduced in comparison to conventional molecular approaches. The results of this study demonstrate the cost-effectiveness and feasibility of a custom-designed targeted NGS panel, and suggest the implementation of targeted NGS into daily routine practice.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The current vitamin D deficiency epidemic is accompanied by an increase in endemic skin cancer. There are still multiple controversies. This review aims to give practical recommendations regarding ...vitamin D among people at risk or with a personal history of skin cancer.
Narrative review including human research articles published between 2011 and 2021, elaborated bearing in mind an epidemiological, patient-centered approach.
Ultraviolet (UV) exposure (neither artificial nor natural) is not the ideal source to synthesize vitamin D. There is conflicting epidemiological evidence regarding vitamin D, non-melanoma skin cancer (NMSC), and cutaneous melanoma (CMM), confounded by the effect of sun exposure and other factors.
Current evidence is controversial, and there are no widely applicable strategies. We propose three practical recommendations. Firstly, sun protection recommendations should be kept among people at risk or with a personal history of skin cancer. Secondly, vitamin D should preferably be sourced through diet. In patients with melanoma or at risk of cutaneous cancer, serum vitamin D checks are warranted to detect and avoid its insufficiency.
TERT promoter mutations in melanoma survival Nagore, Eduardo; Heidenreich, Barbara; Rachakonda, Sívaramakrishna ...
International journal of cancer,
1 July 2016, Volume:
139, Issue:
1
Journal Article
Peer reviewed
Open access
Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at‐risk primary melanoma ...patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression‐free and melanoma‐specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease‐free and melanoma‐specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease‐free survival was 2.3 (95% CI 1.2–4.4) and for melanoma‐specific survival 5.8 (95% CI 1.9–18.3). The effect of the mutations on melanoma‐specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4–15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1–0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.
What's new?
Mutations in the promoter of the TERT gene lead to increases in telomerase activity, prolonged telomere maintenance, and cell immortality. Such mutations are associated with parameters of adverse outcome in different cancer types, including melanoma. Data from this study shows that in primary melanoma, mutations in the TERT promoter together with mutations in BRAF/NRAS are associated with very poor survival and can be used to identify patients at risk of disease relapse and death. The prognostic value of the mutations is potentially improved through inclusion of a common polymorphism harbored within the TERT promoter.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Mutations within the promoter of gene encoding telomerase reverse transcriptase subunit are frequent in many cancers including melanoma. Previously, the TERT promoter mutations were shown to ...associate with markers of poor outcome and reduced survival in patients with primary melanoma. In this study, we investigated the impact of the subtypes of TERT mutations on disease‐free and melanoma‐specific survival in 287 patients with stage I/II nonacral melanoma. Our results showed that of the three TERT promoter mutation subtypes, in multivariate models, the −138/−139 CC > TT tandem mutation associated with worst disease‐free and melanoma‐specific survival. In particular, in combination with BRAF/NRAS mutations, the −138/−139 CC > TT TERT promoter mutation associated with statistically significant poor disease‐free and melanoma‐specific survival with hazard ratios of 6.04 (95% CI 2.03–17.94, p = 0.001) and 12.59 (95% CI 2.18–72.70, p = 0.005), respectively. In contrast to the survival data, luciferase assays showed that the highest activity was observed in experiments with a promoter construct with −124 C > T mutation followed by the −138/−139 CC > TT and −146 C > T mutations, which showed similar activity. Based on previous reports, we speculate that the tandem mutation probably leads to greater genomic instability than the common TERT promoter mutations, hence the association with worst survival. However, the results from the study are only preliminary with limited patient data, therefore, require a cautious interpretation. The observations in this study, if confirmed, could have implications for melanoma patients treated with MAP‐kinase inhibitors.
What's new?
Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are associated with poor outcome and reduced survival in different cancers. Here, subtypes of these mutations were investigated for their impact on survival specifically in melanoma. Among patients with stage I/II melanoma, those with the −138/−139 CC > TT TERT alteration, which occurs primarily in skin cancers, showed the poorest disease‐free and melanoma‐specific survival. The impact on survival was significantly worsened when the −138/−139 CC > TT TERT alteration was combined with BRAF/NRAS mutations. The findings could have implications for melanoma patients treated with MAP‐kinase inhibitors, which interact with BRAF/NRAS signaling networks.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Basal cell carcinoma (BCC) represents the most commonly diagnosed human cancer among persons of European ancestry with etiology mainly attributed to sun-exposure. In this study we investigated ...mutations in coding and flanking regions of PTCH1 and TP53 and noncoding alterations in the TERT and DPH3 promoters in 191 BCC tumors. In addition, we measured CpG methylation within the TERT hypermethylated oncological region (THOR) and transcription levels of the reverse transcriptase subunit. We observed mutations in PTCH1 in 58.6% and TP53 in 31.4% of the tumors. Noncoding mutations in TERT and DPH3 promoters were detected in 59.2% and 38.2% of the tumors, respectively. We observed a statistically significant co-occurrence of mutations at the four investigated loci. While PTCH1 mutations tended to associate with decreased patient age at diagnosis; TP53 mutations were associated with light skin color and increased number of nevi; TERT and DPH3 promoter with history of cutaneous neoplasms in BCC patients. Increased reverse transcriptase subunit expression was observed in tumors with TERT promoter mutations and not with THOR methylation. Our study signifies, in addition to the protein altering mutations in the PTCH1 and TP53 genes, the importance of noncoding mutations in BCC, particularly functional alterations in the TERT promoter.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Sturge-Weber syndrome (SWS) is characterized by port-wine stains (PWS) affecting the face, eyes, and central nervous system. Pulsed dye laser (PDL) is the standard treatment for PWS. ...Unfortunately, recurrence is frequent because of reformation and reperfusion of blood vessels. Objective We sought to assess the clinical efficacy of topical rapamycin combined with PDL in PWS of patients with SWS. Methods We conducted a phase II, randomized, double-blind, intraindividual placebo-controlled, clinical trial. We recruited 23 patients with SWS and facial PWS (12 women; median age 33 years, age range 17-65 years) from the University Clinic of Navarra, Spain. Four interventions were evaluated: placebo, PDL + placebo, rapamycin, and PDL + rapamycin. Clinical and histologic responses were evaluated using a chromatographic computerized system, spectrometry, and histologic analyses at 6, 12, and 18 weeks after the intervention. Results PDL + rapamycin yielded the lowest digital photographic image score and the lowest percentage of vessels in histologic analysis, and showed a statistically significant improvement compared with the other interventions. The treatment was generally well tolerated. Limitations PDL was only applied to the lateral parts of the PWS area. Conclusion Topical rapamycin associated with PDL seems to be an effective treatment for PWS in patients with SWS.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A family history of melanoma greatly increases the risk of developing cutaneous melanoma, a highly aggressive skin cancer whose incidence has been steadily increasing worldwide. Familial melanomas ...account for about 10% of all malignant melanomas and display an inheritance pattern consistent with the presence of pathogenic germline mutations, among which those involving CDKN2A are the best characterized. In recent years, a growing number of genes, such as MC1R, MITF, CDK4, POT1, TERT, ACD, TERF2IP, and BAP1, have been implicated in familial melanoma. The fact that individuals harboring these germline mutations along with their close blood relatives have a higher risk of developing multiple primary melanomas as well as other internal organ malignancies, especially pancreatic cancer, makes cascade genetic testing and surveillance of these families of the utmost importance. Unfortunately, due to a polygenic inheritance mechanism involving multiple low-risk alleles, genetic modifiers, and environmental factors, it is still very difficult to predict the presence of these mutations. It is, however, known that germline mutation carriers can sometimes develop specific clinical traits, such as high atypical nevus counts and specific dermoscopic features, which could theoretically help clinicians predict the presence of these mutations in prone families. In this review, we provide a comprehensive overview of the high- and intermediate-penetrance genes primarily linked to familial melanoma, highlighting their most frequently associated non-cutaneous malignancies and clinical/dermoscopic phenotypes.
Combined Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC) have classically been regarded as more aggressive than conventional, pure, Merkel cell polyomavirus (MCPyV)-positive MCC. It is ...still unknown whether combined MCC and SCC are more aggressive than pure, MCPyV-negative MCC, and the origin of both the SCC and MCC elements of these combined tumors has not been elucidated. The main objective of this systematic review was to assess whether combined MCC and SCC tumors are associated with a worse prognosis than pure MCC; the secondary goals were the characterization of the clinical and histopathological features of these combined neoplasms. A total of 38 studies, including 152 patients, were selected for review. In total, 76% of the cases were MCPyV-negative, whereas 4% were MCPyV-positive. The most frequent histopathological pattern was that of an SCC in situ combined with a dermal MCC (36%), followed by both an in situ and invasive SCC combined with a dermal MCC (20%). Forty-seven percent of all cases fitted in the morphology of the so-called "collision tumors". Three combined MCC cases that would fit in the morphological category of collision tumors presented both squamous and neuroendocrine elements in their respective nodal metastases. The mean overall survival was 36 months, comparable to that of pure, MCPyV-negative MCC. This review found similarly aggressive behavior for combined MCC and SCC and pure, MCPyV-negative MCC. Preliminary data strongly suggest that all MCPyV-negative MCC tumors, whether combined or pure, are part of a common spectrum.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
PDF
