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 polarised light and can be used to help distinguish melanomas from benign lesions. Dermatoscopy images with a confirmed diagnosis can be utilized to develop artificial intelligence as a medical device (AIaMD) tool. This contribution discusses the utilization of artificial intelligence (AI) in melanoma management and describes an AIaMD tool that has been used in current UK clinical practice on over 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.

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.

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.

Current prescribing for pyoderma gangrenosum in the UK and access to biologic medications: Results from a UK Dermatology Clinical Trials Network (UKDCTN) survey of UK Dermatologists.

Pyoderma gangrenosum (PG) is an ulcerative inflammatory disorder affecting the lower legs in 80% of cases. 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 NHS, 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%). Biologics have been used by 66% of clinicians as second line therapy but 19% 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.

British Royalty and Aristocracy: Their skin maladies Part II. Queen Mary II's death from hemorrhagic smallpox.

In 1694, Queen Mary II (1662-1694) died at age 32 of hemorrhagic smallpox, a rare and fatal form of the viral infection. This contribution presents the clinical features of Queen Mary II's smallpox infection. It also reviews, from a modern-day perspective, the disseminated intravascular coagulopathy involved in the pathophysiology of hemorrhagic smallpox, which is characterized by thrombocytopenia, coagulation factor deficiency, and hypofibrinogenemia.

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.

'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.

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.

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.

Follow-up of Patients With Keratinocyte Carcinoma: A Systematic Review of Clinical Practice Guidelines.

Importance: Patients treated for cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), collectively called keratinocyte carcinoma (KC), are at risk for recurrence, metastasis, and additional primary cutaneous malignant neoplasms. It is unclear how often patients should be seen for follow-up skin examination after initial treatment of KC. Objective: To summarize the recommendations and evaluate the methodological quality of clinical practice guidelines for dermatologic follow-up of patients with BCC and invasive SCC. Evidence Review: PubMed, MEDLINE, and Embase were searched for relevant articles published from January 2010 to March 2022. Search terms included guideline, squamous cell carcinoma, and basal cell carcinoma. National or international guidelines containing recommendations for follow-up frequency after a diagnosis of localized cutaneous KC were included. Quality was assessed using the 6 domains of the Appraisal of Guidelines Research and Evaluation II (AGREE II) tool: (1) scope and purpose; (2) stakeholder development; (3) rigor of development; (4) clarity of presentation; (5) applicability; and (6) editorial independence. The Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) was used to guide study reporting. Findings: Among the 14 guidelines meeting eligibility criteria, there was little consensus on the appropriate follow-up frequency after initial KC treatment. Overall duration of follow-up ranged from a single posttreatment visit to lifelong surveillance. Most guidelines stratified their recommendations by recurrence risk. For low-risk BCC and guidelines that did not stratify by risk, follow-up recommendations ranged from every 6 to 12 months. For high-risk BCC, 1 guideline suggested follow-up every 3 months, while 4 recommended every 6 months. For low-risk SCC, 5 guidelines recommended annual follow-up; 3 guidelines, every 6 months; and 1 guideline, every 3 months. For high-risk SCC, recommendations included a range of follow-up frequencies, spanning every 3 months (n = 5 guidelines), 4 months (n = 1), 6 months (n = 6), or annually (n = 4). One guideline did not use risk stratification and recommended annual screening. The highest scoring AGREE II domain was "scope and purpose," which assessed the guideline's overall objectives, and the lowest scoring was "applicability," which assessed barriers and facilitators to implementation. Conclusions and Relevance: The findings of this systemic review highlight variations in follow-up recommendations for patients after initial treatment for KC. Randomized clinical trials are needed to define an optimal follow-up regimen.

NHS outpatient secondary care: a time of challenges and opportunities.

The English NHS outpatient service was handling over 1.6 million referrals per month before the COVID-19 pandemic, with numbers growing each year. There was a fall during the pandemic but by 2022, referrals were close to pre-pandemic levels. The GIRFT programme clinical leads from over 41 specialties visited each English hospital to identify unwarranted variation in care and identify good practice. A wealth of innovations covering the whole outpatient journey were identified in the national reports, which are published on the GIRFT website. Patient needs and demands vary greatly between infants and the elderly, between mental health, medical and surgical specialties. However, it was remarkable how common themes bridged age and illness to identify again and again how services could be improved. This report summarises the key themes identified by GIRFT to improve outpatient services in England as it moves forwards from the COVID pandemic.

Dermatographism in popular culture.

Dermatographism was first described by William Heberden (1710-1801) more than 250 years ago as a type of urticaria brought on by rubbing or scratching the skin. In 1859, William Gull (1816-1890) gave it the name factitious urticaria, distinguishing dermatographism from chronic urticaria, in which the skin lesions appear spontaneously. During the 1870s French physicians at the Salpetriere Hospital in Paris became impressed by their ability to write words on the bodies of patients admitted with hysteria and other psychiatric disorders, who also exhibited dermatographism. At first, they described this phenomenon as "autographisme," but by 1890 it became known as "dermographisme," the forerunner of the current term "dermatographism." At the Salpetriere and elsewhere in the world, it became fashionable to photograph patients with dermatographism, to capture the striking urticarial writing on their skin. These photographs were used in atlases and to illustrate dermatology texts and medical journals as well as popular magazines. This contribution presents several vintage photographs of dermatographism from the late 19th century to the early 20th century. Dermatographism has also become featured in popular culture including film, comic books, poetry, and body art, examples of which are provided in this contribution with the assistance of two of our authors, Ariana Page Russell and Jeannine Hall Gailey, who have embraced their dermatographism and have used their artistic and poetic talents to educate and inspire patients about this common skin condition.

British Royalty and Aristocracy: Their skin maladies Part I. Winston Churchill: Wartime skin graft donor.

Following the 1898 Battle of Omdurman in Sudan, Winston Churchill, then a second lieutenant in the British army, donated a skin graft to Richard Molyneux, a wounded fellow officer. This contribution tells the story of Churchill's skin graft donation within the context of the development of skin grafting as a viable treatment for serious wounds and burns.