A genome-wide meta-analysis of palmoplantar pustulosis implicates TH2 responses and cigarette smoking in disease pathogenesis.

BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. Although the disease can present with concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets. OBJECTIVES: We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis. METHODS: We performed a genome-wide association meta-analysis of 3 North-European cohorts (n = 1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP. RESULTS: We found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P < 5 × 10-6) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and TH2-mediated diseases such as atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP. CONCLUSIONS: The first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.

Current prescribing for pyoderma gangrenosum in the UK and access to biologic medications: results from a UK Dermatology Clinical Trials Network survey of dermatologists.

Pyoderma gangrenosum (PG) is an ulcerative inflammatory disorder affecting the lower legs in 80% of patients. The use of biologic medications to treat PG is increasing, although there is a limited evidence base to guide treatment choices. In some health systems, such as the UK National Health Service, limitations are placed on biologic prescribing for PG, leading to wide variations in prescribing. A survey of mainly UK clinicians showed that prednisolone remains the first-line treatment for PG (90%, 34/38). Biologics have been used by 66% (25/38) of clinicians as second-line therapy, but 19% (7/38) have had prescribing requests declined. Further research is needed to determine optimal treatment strategies for PG.

Lentigo maligna: a review.

Lentigo maligna (LM) is a melanoma in situ with distinct clinical features and histology. It commonly affects men after the sixth decade of life. Incidence rates of LM have increased based on early 21st century data from different countries; however, data are suboptimal. Data from England show a plateauing crude incidence between 2013 and 2019. By comparison, invasive melanoma and other types of melanoma in situ commonly appears in younger age groups (median age 58 and 67 years old, respectively) and incidence is rising. The most important risk factors for LM include fair skin and cumulative ultraviolet solar radiation exposure. Although LM is limited to the epidermis and connected skin adnexa, it may progress to invasive LM melanoma. The reported rate of malignant progression varies, reflecting a challenge for LM epidemiology research as often lesions are removed on diagnosis. LM poses a challenge in diagnosis and management. Although it can be diagnosed clinically or dermoscopically, histopathological assessment of biopsied skin tissue remains the gold standard. Reflectance confocal microscopy allows for better appreciation of the complexity of LM at a cellular level, often progressing beyond clinical margins. Management of LM may involve Mohs micrographic surgery or excision, although recurrence may occur even with 5 mm clinical margins. Imiquimod cream may be effective, but incomplete treatment and recurrence has been reported. Conservative management with observation or radiotherapy may be used in selected patients' cases. Five-year net survival rates are excellent. This paper reviews the natural history, epidemiology, aetiology, pathogenesis, diagnosis and management of LM.

Cutaneous melanoma in situ: a review.

Cutaneous melanoma in situ (MIS), also known as 'stage 0 melanoma', is a collection of malignant melanocytes in the epidermis and epithelial adnexa, without evidence of microinvasion to the papillary dermis. Distinct histologic subtypes include lentigo maligna (LM), superficial spreading (SS) MIS and acral lentiginous (AL) MIS. LM is the most common subtype, usually diagnosed later in life (median age at diagnosis of 66-72 years) and associated with cumulative ultraviolet radiation exposure. SS MIS is associated with intense episodes of sun exposure and is more common on the trunk and extremities. AL MIS is seen in non-hair-bearing skin. Although rare (0.6% of MIS in England), AL MIS is found in higher proportion in more pigmented skin types compared to other MIS subtypes. Most international studies between 1990-2019 report rising incidence for MIS. US data support a deceleration in the rising incidence of LM between 2016-2019. For 2013-2019 in England, the recorded incidence of LM is plateauing, while that of other MIS is rising. Definitive diagnosis of MIS is by histological examination of biopsied skin with immunohistochemistry but can be supported with dermoscopy and reflectance confocal microscopy. Surgical treatment (excision or Mohs micrographic surgery) is the gold standard. Depending on MIS subtype, other options such as cryotherapy, topical imiquimod, radiotherapy, or watchful waiting may be appropriate. The latest 5-year net survival rates in England between 2013-2015 are 98.6% for AL MIS and exceed 100% for all other MIS. This review summarises the aetiology, pathogenesis, epidemiology, diagnosis and management of MIS.

Trends in incidence, treatment and survival of Merkel cell carcinoma in England 2004-2018: a cohort study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare tumour with neuroendocrine differentiation and high associated mortality. Studies that describe the epidemiology of MCC are often limited by small sample size, short duration of follow-up, absence of nationwide data and paucity of data on different risk factors. OBJECTIVES: To determine the incidence, demographics and survival for MCC in England between 2004 and 2018. METHODS: This national retrospective cohort study identified all cases of MCC in England from 2004 to 2018 using national population-based data from the National Disease Registration Service. Crude counts, European age-standardized incidence rates (EASRs) and joinpoint analysis were conducted. Patient demographics and treatments received were described. Multivariable Cox regression analysis was used to study risk factors for MCC-specific mortality, by including a priori defined demographic factors, tumour characteristics and immunosuppression. Treatment data were not included in the Cox regression analysis. RESULTS: A total of 3775 MCC tumours were registered. The median age at diagnosis was 81 years (interquartile range 74-87). Overall, 96·6% of patients identified as White ethnicity, and 8·3% of patients were immunosuppressed. The most common site was the face (27·4%). Patients most often presented with stage one disease (22·8%); however, stage was unknown in 31·0%. In total, 80·7% of patients underwent surgical excision, 43·5% radiotherapy and 9·2% systemic therapy. The EASR increased from 0·43 per 100 000 person-years (PYs) to 0·65 per 100 000 person-years between 2004 and 2018, representing a significant annual percentage change of 3·9%. The EASR was greater in men than in women for all years, with an overall male-to-female ratio of 1·41 : 1. The highest EASR was in South West England. Five-year disease-specific survival was 65·6% [95% confidence interval (CI) 63·8-67·4], with a median follow-up of 767 days. MCC-specific mortality increased with age [hazard ratio (HR) 1·02, 95% CI 1·02-1·03], deprivation (HR 1·43, 95% CI 1·16-1·76), immunosuppression (HR 2·80, 95% CI 2·34-3·34) and stage at diagnosis (HR 8·24, 95% CI 5·84-11·6). CONCLUSIONS: This study presents the largest national MCC dataset in Europe, and the most complete reporting of MCC incidence and survival ever published. With the EASR of MCC increasing and high associated mortality, this study encourages further research into the pathology, diagnosis and therapeutic options for MCC to support management guidelines.

'Get Data Out' Skin: national cancer registry incidence and survival rates for all registered skin tumour groups for 2013-2019 in England.

BACKGROUND: Providing detailed skin cancer statistics, including incidence and survival, by tumour type and patient characteristics is important for up-to-date epidemiological information. OBJECTIVES: To create a new clinically relevant consensus-based classification for registered skin tumours using tumour type and patient characteristics and to describe its application to all registered tumours in England between 2013 and 2019. METHODS: Tumours with skin topographical codes (ICD-10) and morphology and behaviour (ICD-O3) were grouped together in an iterative process creating a hierarchical tree structure. The primary-level grouping partitioned skin tumours into skin cancer, melanoma in situ, extramammary Paget disease (EMPD) and tumours of uncertain malignant potential. Second-level groups split skin cancer into keratinocyte cancer (KC), melanoma and rare cancers. The third-level group split KC into basal cell carcinoma (BCC) and squamous cell carcinoma (cSCC). Further groups were split into genital or non-genital, first or subsequent tumour, age, gender, stage, or National Health Service (NHS) region. Incidence counts, Kaplan-Meier and net survival estimates and referral routes [two-week wait (TWW), general practitioner (GP), outpatient] categorisations were calculated for each grouping across all years. RESULTS: A total of 1 445 377 skin cancers and 49 123 precancerous lesions and undefined entities were registered in England between 2013 and 2019. Skin tumours and skin cancer incidence rates are increasing for most tumour types. The most common type of skin cancer was BCC with an incidence rate of 282.36 per 100 000 person-years (PYs) [n = 158 934, 95% confidence interval (CI) 280.98-283.76] in 2019, followed by cSCC with an incidence rate of 85.24 per 100 000 PYs (n = 47 977, 95% CI 84.48-86.00) and melanoma with 27.24 (n = 15 332, 95% CI 26.81-27.67) per 100 000 PYs. Each year approximately 1800 rare skin cancers, 1500 genital cSCCs and 100 cases of EMPD are registered. Of 15 000 melanoma cases, 120 cases of melanoma occur in individuals aged < 25 years annually. One-year and five-year overall net survival varies by tumour type. cSCC 5-year net survival (89.8%, 95% CI 88.8-90.9) was comparable to the net survival of all melanomas (89.6%, 95% CI 88.7-90.6). BCC had excellent survival (overall net survival > 100%). Patients with late-stage melanoma, Merkel cell carcinoma and genital cSCC have a 5-year net survival < 60%. Older patients received fewer TWW referrals than their younger counterparts with the same tumour type at the same location. Patients with acral lentiginous melanoma had fewer TWW referrals and more standard GP referrals than patients with common melanomas. CONCLUSIONS: 'Get Data Out' Skin provides detailed and up-to-date statistics on all registrable skin tumours in England, including for the first time precancerous lesions and rare subtypes of common cancers. These data can be used by clinicians, researchers and commissioners to better understand skin cancer and improve resource allocation.

Review of dermatofibrosarcoma protuberans.

The clinical features, histological subtypes and management of dermatofibrosarcoma protuberans (DFSP) are reviewed in this article. DFSP is an uncommon cutaneous sarcoma first described in 1890. It has a high local recurrence rate, low metastatic rate and low mortality. The crude incidence rate in England in 2019 was reported as 3.0 per million person-years. A fusion of platelet-derived growth factor subunit B (PDGFB) and COL1A1, t(17;22)(q22;q13), has been found in over 90% of people with DFSP. This fusion is thought to upregulate PDGFB expression, stimulating cell growth by activation of Ras mitogen-activated protein kinases and PI3K-AKT-mTOR, potentiating oncogenesis. DFSP usually presents as an asymptomatic flesh-coloured, thickened, rubbery plaque or nodule with an uneven surface. The most common sites are the trunk followed by lower limbs, head and neck and upper limbs. Larger tumours can infiltrate underlying local structures and around 1% metastasize. Key histological features in DFSP are spindle cells arranged in a storiform pattern with intense CD34 staining. Histological subtypes include classical DFSP, Bednar, myxoid, giant cell fibroblastoma, atrophic and DFSP-fibrosarcomatous. The gold standard management for localized tumours is surgical: current recommendations favour Mohs micrographic surgery over wide local excision. Adjuvant radiotherapy may be offered after surgery. Imatinib can be used as neoadjuvant therapy and in patients with inoperable or metastatic tumours. Further research should be conducted to better understand pathogenesis of DFSP, identify associated risk factors and standardize management.

Epidemiology of porocarcinoma in England 2013-2018: a population-based registry study.

BACKGROUND: Porocarcinoma (PC) is a cutaneous malignancy that differentiates towards (possibly arises from) the sweat ducts and glands. Lack of histological diagnostic markers makes clinical and pathological diagnosis complex. The limited data available suggest the incidence is increasing; however, this remains to be established in national epidemiological studies. OBJECTIVES: To report the incidence, treatment and survival of patients with PC in England from 1 January 2013 to 31 December 2018 using national cancer registry data. METHODS: PC diagnoses in England during 2013-2018 were identified from the National Disease Registration Service using morphology and behaviour codes. These were registered from routinely collected pathology reports and cancer outcomes and services datasets. The 2013 European age standardized incidence rates (EASRs), Kaplan-Meier all-cause survival and log-rank test were calculated. RESULTS: In total, 738 tumours (396 in males and 342 in females) were diagnosed. The median age at diagnosis was 82 years old (interquartile range 74-88). The most frequently affected site were lower limbs (35.4%), followed by the face (16%). The majority of the cohort received surgical excision (73.0%). The Kaplan-Meier all-cause survival was 45.4% at 5 years, which was lower than in previous studies. The EASR for the whole population was 0.25 [95% confidence interval (CI) 0.23-0.27] per 100 000 person-years (PY)]. PC incidence rates in the East of England (EASR of 0.54, 95% CI 0.47-0.63 per 100 000 PY) were three times higher than the South West (EASR of 0.14, 95% CI 0.10-0.19 per 100 000 PY) where the regional rates were the lowest. CONCLUSIONS: This study shows that there is large variation in the EASRs of PC across England. This may reflect differences in how PC is diagnosed and registered in different regions in England. These data support national assessment of the management of PC, which will inform future studies and guideline development.

Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis.

BACKGROUND: Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat. OBJECTIVE: We sought to investigate the immune pathways that underlie the pathogenesis of PPP. METHODS: We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several TH2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4+ T cells of PPP patients were skewed toward a TH17 phenotype, a phenomenon that was particularly significant among cutaneous lymphocyte-associated antigen-positive skin-homing cells. We also identified a subset of memory CD4+ T cells that expressed both TH17 (KLRB1/CD161) and TH2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of TH17 to TH2 plasticity. Interestingly, the GATA3+/CD161+ cells were overrepresented among the peripheral blood mononuclear cells of affected individuals, both in the single-cell RNA-Seq data set and in independent flow cytometry experiments. Dual-positive cells were also detected in patient skin by immune fluorescence microscopy. CONCLUSIONS: PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.

Porocarcinoma: a review.

From the first report in 1969 to the present day, diagnosis of eccrine porocarcinoma, also known simply as porocarcinoma (PC), remains a challenge. This review presents a concise update of the history, pathogenesis, epidemiology, diagnosis, management and prognosis of this rare sweat gland neoplasm. PC differentiates towards the intraepidermal spiral ducts in the eccrine gland, is more common in people aged > 60 years and often affects the head, neck and legs. PC presents as a dome-shaped papule, plaque or nodule growing over weeks to months. The exact incidence of PC is unknown but appears to be rising. Diagnosis is difficult because of variable presentations and similar clinical and histological features to cutaneous squamous cell carcinoma. Management involves removal of the tumour, usually using wide local excision or Mohs micrographic surgery. Prognosis is poor, with PC recurring after surgery in 35% of cases. Given the lack of standardized protocols and risk profiles, further studies would help improve the understanding of PC.

Artificial intelligence and skin melanoma.

Melanoma is the deadliest skin cancer, presenting typically with changing pigmented areas and usually treated with surgical removal. As benign cutaneous pigmented lesions are very common in all populations, it can be challenging to identify which areas should be cut out or left untreated. Delayed treatment in melanoma increases the risk of death, but it is not possible to remove all lesions. Dermatoscopy uses polarized light and can be used to help distinguish melanomas from benign lesions. Dermatoscopy images with a confirmed diagnosis can be used to develop artificial intelligence (AI) as a medical device (AIaMD) tool. This contribution discusses the utilization of AI in melanoma management and describes an AIaMD tool used in current UK clinical practice on more than 80,000 patients. This is a springboard for discussing the scope, risks, and mitigations for future AI use by all clinicians involved in managing people with melanoma.

Impact of the COVID-19 pandemic on international cutaneous squamous cell carcinoma incidence: A systematic review and meta-analysis.

Background: Non-melanoma skin cancer (NMSC) is the most common cancer globally in white ethinicity populations, and cutaneous squamous cell carcinoma (cSCC) is the second most common subtype. The COVID-19 pandemic severely impacted public and private healthcare systems. Many studies have reported reduced cancer diagnoses during the pandemic. The impact of the COVID-19 pandemic on global cSCC and NMSC incidence is poorly reported. Objectives: The aim was to conduct a systematic review and meta-analysis to assess the impact of the COVID-19 pandemic on global cSCC and NMSC incidence rates, compared with 2019 incidence rates. Two primary outcome measures were used: crude incidence rate ratios (CIRR) and age-standardised incidence rate ratios (ASIRR). Methods: A structured search was undertaken on 23 March 2023 using grey literature and four electronic databases: MEDLINE, CINAHL, EMBASE and Web of Science. Studies published before January 2020 were excluded. A quality assessment was undertaken using A. Lomas quality assessment tool. CIRR outcomes were synthesised in a meta-analysis, while ASIRR outcomes were narratively synthesised. Results: Fourteen cancer registries were included, capturing data from 13 countries across Europe. Variation was observed in NMSC and cSCC incidence across the cancer registries. Pooled cSCC crude incidence rates in 2020 were equal to crude incidence rates in 2019 (cSCC-CIRR 1.00 (95% confidence interval (CI) 0.94-1.06). In 2021, the pooled result indicated a non-significant 8% increase in cSCC crude incidence rates, compared with 2019 (cSCC-CIRR 1.08 (95% CI 0.98-1.19). Significant reductions were reported in NMSC incidence across all meta-analyses in 2020 and 2021 compared with 2019. Heterogeneity was observed across most pooled estimates (I 2>75%). Conclusion: There was a lack of high quality data on cSCC incidence rates recorded during the pandemic outside of Europe. The COVID-19 pandemic resulted in no significant changes in cSCC incidence across Europe. By contrast, NMSC incidence fell across Europe following the pandemic. Significant reductions in pooled NMSC incidence rates may reflect a delay in basal cell carcinoma presentation, diagnosis and treatment. Although annual incidence rates for cSCC were not affected by the pandemic, delays in treatment may still have occurred, which may result in poorer outcomes yet to be fully understood.

International time trends and differences in topical actinic keratosis therapy utilization.

Background: Actinic Keratoses (AK) are precancerous lesions that can lead to Squamous Cell Carcinoma. International differences in the utilization of topical medications to treat AK are not well described. Objectives: To describe international differences in topical AK medication utilization, including associations of countries' economic status with AK medication utilization. Methods: We used IQVIA MIDAS pharmaceutical sales data for 65 countries (42 high-income, 24 middle-income) from April 2011 to December 2021. We calculated each country's quarterly utilization of medications in grams per 1000 population. We used univariable linear regression to assess the association between country economic status and AK medication utilization. Results: High-income countries used 15.37 more grams per 1000 population of 5-fluorouracil (95% CI: 9.68, 21.05), 4.64 more grams per 1000 population of imiquimod (95% CI: 3.45, 5.83), and 0.32 more grams per 1000 population of ingenol mebutate (95% CI: 0.05, 0.60). Limitations: Missing medication utilization data for some countries. Conclusion: High-income countries use more topical AK therapies than middle-income countries.