Melanoma predilection for the lower limbs of women compared with men.

The lower limb is a common site for melanoma in women, but the reason for this is not fully understood. To investigate this phenomenon in more detail, we assessed the specific subsites of primary melanoma occurring on the lower limbs of females compared with males across age groups. In a records-based study at an oncology hospital in north-west of England, among an unselected sample of patients with primary invasive melanoma treated between 2002-2015, information was collected on patient age at diagnosis, sex, and co-morbidities, and the tumor thickness and anatomical subsite (thigh, lower leg, foot for lower limb). Of a total sample of 1,522 patients, 316 (227, 72% female) had lower limb melanoma. The most common subsite was lower leg (142 cases with F:M ratio =3.74), followed by thigh (55 cases with F:M = 1.83) and feet (30 cases with F:M = 1.15). At ages <40 years the odds of thigh to foot melanoma was 20 times higher in females than in males (OR 20.0, 95% CI 2.6-152.6) and 7.5 times higher on the lower limb (OR 7.5, 95% CI 1.1-49.2). For ages 40+ years, the odds of females developing thigh melanoma compared to foot melanoma was similar in males versus females (OR 0.8), while the corresponding odds of lower leg melanoma in females versus males remained significantly increased at ages 40-59 and 60+ (OR 4.2 and 2.8 respectively). Our study demonstrates the female predilection for lower limb melanoma persists over most but not all subsites.However, there is heterogeneity in the female to male occurence of lower limb melanoma across subsites and at different ages, which may be linked to relative influence of genetic and environmental risk factors.

Higher mycophenolate dosage is associated with an increased risk of squamous cell carcinoma in kidney transplant recipients.

BACKGROUND: Kidney transplant recipients are at increased risk of keratinocyte cancers, namely squamous cell and basal cell carcinomas (SCCs and BCCs). This is primarily due to the high levels of immunosuppression that are required to prevent allograft rejection. Different immunosuppressive medications confer different risks, and the effect of mycophenolate mofetil on SCC and BCC risk is unclear. We explored the relationship between mycophenolate dose prescribed over the entire transplant period and the risk of SCC and BCC. METHODS: Kidney transplant recipients from Queensland, Australia, were recruited between 2012 and 2014 and followed until mid-2016. During this time transplant recipients underwent regular skin examinations to diagnose incident SCCs and BCCs. Immunosuppressive medication regimens were obtained from hospital records, and the average mycophenolate dose/day over the entire transplantation period was calculated for each patient. Doses were divided into three ranked groups, and adjusted relative risks (RRadj) of developing SCC and BCC tumours were calculated using negative binomial regression with the lowest dosage group as reference. Recipients who had used azathioprine previously were excluded; further sub-group analysis was performed for other immunosuppressant medications. RESULTS: There were 134 kidney transplant recipients included in the study. The average age was 55, 31% were female and 69% were male. At the highest median mycophenolate dose of 1818 mg/day the SCC risk doubled (RRadj 2.22, 95% CI 1.03-4.77) when compared to the reference group of 1038 mg/day. An increased risk persisted after accounting for ever-use of ciclosporin, ever-use of tacrolimus, and when excluding mammalian target of rapamycin users. This increased risk was mainly carried by kidney transplant recipients immunosuppressed for five or more years (RRadj = 11.05 95% CI 2.50-48.81). In contrast, there was no significant association between BCC incidence and therapy with the highest compared with the lowest mycophenolate dosage (RRadj = 1.27 95% CI 0.56-2.87). CONCLUSION: Higher mycophenolate dosage is associated with increased SCCs in kidney transplant recipients, particularly those immunosuppressed for more than five years. The increased SCC risk persists after accounting for usage of other immunosuppressant medications.

Polygenic risk score as a determinant of risk of keratinocyte cancer in an Australian population-based cohort.

BACKGROUND: Keratinocyte cancer (KC) risk is determined by genetic and environmental factors. Genetic risk can be quantified by polygenic risk scores (PRS), which sum the combined effects of single nucleotide polymorphisms (SNPs). OBJECTIVES: Our objective here was to evaluate the contribution of the summed genetic score to predict the KC risk in the phenotypically well-characterized Nambour population. METHODS: We used PLINK v1.90 to calculate PRS for 432 cases, 566 controls, using 78 genome-wide independent SNPs that are associated with KC risk. We assessed the association between PRS and KC using logistic regression, stratifying the cohort into three risk groups (high 20%, intermediate 60%, low 20%). RESULTS: The fully adjusted model including traditional risk factors (phenotypic and sun exposure-related), showed a significant 50% increase in odds of KC per standard deviation of PRS (odds ratio (OR) = 1.51; 95% confidence interval (CI) = 1.30-1.76, P = 5.75 × 10-8 ). Those in the top 20% PRS had over three times the risk of KC of those in the lowest 20% (OR = 3.45; 95% CI = 2.18-5.50, P = 1.5 × 10-7 ) and higher absolute risk of KC per 100 person-years of 2.96 compared with 1.34. Area under the ROC curve increased from 0.72 to 0.74 on adding PRS to the fully adjusted model. CONCLUSIONS: These results show that PRS can enhance the prediction of KC above traditional risk factors.

Diet quality is associated with primary melanoma thickness.

BACKGROUND: Patients' diets can influence the outcome of several common cancers, but the effect on melanoma prognosis is unknown. OBJECTIVE: To assess the association between quality of melanoma patients' prediagnosis diets and primary tumour thickness, the main prognostic indicator for melanoma. METHODS: We used baseline data from patients newly diagnosed with tumour stage Ib to IV cutaneous melanoma, with completed questionnaires about food intake in the past year and other factors. Diet quality was measured by the Healthy Eating Index (HEI) and melanoma thickness was extracted from histopathology reports. We estimated prevalence ratios (PRadj ) and 95% confidence intervals (CIs) adjusted for confounding factors using Poisson regression models to assess associations between HEI scores and melanoma thickness. RESULTS: Of 634 study patients, 238 (38%) had melanomas >2 mm thick at diagnosis. Patients with the highest HEI scores were significantly less likely to be diagnosed with thick melanoma than patients with lowest HEI scores (PRadj 0.93, 95% CI 0.86-0.99) (Ptrend = 0.03). There was no evidence of effect modification by age, sex, previous melanoma or comorbidities. CONCLUSIONS: Melanoma thickness at diagnosis is significantly associated with quality of patients' diets before diagnosis.

High variability in anatomic patterns of cutaneous photodamage: a population-based study.

BACKGROUND: Skin cancer is strongly associated with photodamaged skin, but body sites are often referred to as 'exposed' or 'unexposed' to sun without recognizing extent of site-specific variation. OBJECTIVES: To assess whole-body patterns of photodamage in an Australian population. METHODS: A random sample of adult residents of Queensland underwent imaging across 10 body sites. Photodamage was graded from images using an ordinal photonumeric scale. We used cluster analysis to identify whole-body photodamage patterns and prevalence proportion ratios (PPRs) to assess associated factors. RESULTS: Of 190 adults (median age 52; 58% males), 58% showed severe or moderate-to-severe photodamage on most body sites. A higher proportion of woman had severe photodamage on the arms (upper: P = 0.002, lower: P = 0.034). A higher proportion of men had moderate or severe photodamage on the lower back (P = 0.004). We identified four photodamage patterns: 'severe general' (n = 24, 13%), 'moderate-severe general' (n = 86, 45%), 'moderate-severe v-neck' (n = 40, 21%) and 'mild-moderate upper body' (n = 12, 6%). All participants with 'severe-general' photodamage were >50 years and more likely to have past skin cancer (PPR: 2.54, 95% CI: 1.44-4.49) than those with 'moderate-severe v-neck' photodamage. Those with 'moderate-severe general' photodamage showed similar associations and were more likely female (PPR: 1.33, 95% CI: 1.04-1.69). Past or current smoking was associated with having higher levels of photodamage, with no smokers in those with 'mild-moderate upper body' photodamage. CONCLUSIONS: Moderate-to-severe photodamage across much of the body is common in Queensland adults and associated with age, sex, past skin cancer and smoking. Assuming a universal pattern of site-specific sun exposure could lead to spurious correlations, while accurate and objective assessment of site-specific photodamage can add to understanding of the development of sun-associated skin cancers, in particular site-specific skin carcinogenesis. Additionally, degree of site-specific photodamage has the potential to assist skin cancer screening.

Clinical utility of skin cancer and melanoma risk scores for population screening: TRoPICS study.

BACKGROUND: Screening for skin cancer can be cost-effective if focused on high-risk groups. Risk prediction tools have been developed for keratinocyte cancers and melanoma to optimize advice and management. However, few have been validated in a clinical setting over the past few years. OBJECTIVES: To assess the clinical utility of risk assessment tools to identify individuals with prevalent skin cancers in a volunteer-based screening clinic. METHODS: Participants were adults presenting for a skin check at a volunteer-based skin cancer screening facility. We used previously published tools, based on questionnaire responses, to predict melanoma and keratinocyte cancers [KCs; basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] and classified each participant into one of five risk categories. Participants subsequently underwent a full skin examination by a dermatologist. All suspicious lesions were biopsied, and all cancers were histopathologically confirmed. RESULTS: Of 789 people who presented to the clinic, 507 (64%) consented to the study. Twenty-two BCCs, 19 SCCs and eight melanomas were diagnosed. The proportion of keratinocyte cancers diagnosed increased according to risk category from <1% in the lowest to 24% in the highest risk category (P < 0.001). Subtype analysis revealed similar proportionate increases in BCC or SCC prevalence according to risk category. However, a similar proportion of melanoma cases were detected in the low-risk and high-risk groups. CONCLUSION: The risk prediction model for keratinocyte cancers can reliably identify individuals with a significant skin cancer burden prior to a skin examination in the community setting. The prediction tool for melanoma needs to be tested in a larger sample exposed to a wider range of environmental risk factors.

Global evidence on occupational sun exposure and keratinocyte cancers: a systematic review.

Individual studies have suggested that the association between occupational exposure to solar ultraviolet radiation (UVR) and the development of keratinocyte cancers (KCs) may only be valid in populations of European ancestry living in certain geographical regions. Comparative global data are scarce and so this review aimed to summarize current evidence on the association between occupational exposure to solar UVR and the development of KCs, with a specific focus on geographical location and skin colour. Ovid MEDLINE, PubMed, Embase and Web of Science were searched for potentially relevant records. Extracted data were summarized by study, country and region. We included one prospective cohort study and 18 case-control studies (n = 15 233) from 12 countries in regions where the majority of the population is white skinned (Americas, Europe and Oceania). Eighteen of the 19 studies reported effect estimates suggesting an increased risk of basal cell carcinoma (BCC) and/or squamous cell carcinoma (SCC) among outdoor workers. Only 11 studies found a significantly increased risk and many had imprecise estimates. There was a significantly increased risk of BCC and SCC in individual studies in North America, Latin America and the Caribbean, Western Europe and Southern Europe, but not across regions or countries. Overall, 95% of studies reported higher risks among outdoor workers, although the increases in risk were statistically significant in just over half of the studies. Well-designed and sufficiently powered occupational case-control and cohort studies with adequate adjustment for confounding factors and other risk factors are required to provide more accurate risk estimates for occupational KC.

Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Statins may reduce disease recurrence in patients with ulcerated primary melanoma.

BACKGROUND: Statins may restrict the cellular functions required for melanoma growth and metastasis. OBJECTIVES: To determine whether long-term statin use commenced before diagnosis of a primary melanoma is associated with reduced risk of melanoma recurrence. METHODS: We prospectively followed a cohort of patients newly diagnosed between 2010 and 2014 with localized tumour-stage T1b to T4b melanoma in Queensland, Australia. We used Cox regression analyses to examine associations between long-term statin use and melanoma recurrence for the entire cohort, and then separately by sex and by presence of ulceration, due to evidence of effect modification. RESULTS: Among 700 patients diagnosed with stage T1b to T4b primary melanoma (mean age 62 years, 59% male, 28% with ulcerated tumours), 94 patients (13%) developed melanoma recurrence within 2 years. Long-term statin users (n = 204, 29%) had a significantly lower risk of disease recurrence than nonusers [adjusted hazard ratio (HRadj ) 0·55, 95% confidence Interval (CI) 0·32-0·97] regardless of statin subtype or potency. Compared with nonusers of statins, risk of recurrence was significantly decreased in male statin users (HRadj 0·39, 95% CI 0·19-0·79) but not in female statin users (HRadj 0·82, 95% CI 0·29-2·27) and in statin users with ulcerated (HRadj 0·17, 95% CI 0·05-0·52) but not nonulcerated (HRadj 0·91, 95% CI 0·46-1·81) primary melanoma. CONCLUSIONS: Statins commenced before melanoma diagnosis may reduce the risk of melanoma recurrence, especially in men and in those with ulcerated tumours. Clinical trial evaluation of the potential role of statins in improving the prognosis of high-risk melanoma is warranted.

Indoor tanning prevalence after the International Agency for Research on Cancer statement on carcinogenicity of artificial tanning devices: systematic review and meta-analysis.

BACKGROUND: Exposure to artificial tanning devices is carcinogenic to humans, and government regulations to restrict or ban indoor tanning appear to be increasing. OBJECTIVES: We evaluated changes in the international prevalence of indoor tanning among adolescents and adults after artificial tanning devices were classified as carcinogenic by the International Agency for Research on Cancer (IARC) in 2009. METHODS: Systematic searches in PubMed and Web of Science databases were undertaken. Overall, 43 studies reporting 'ever' or 'past-year' indoor tanning exposure after 2009 were identified. We used metaregression analysis to evaluate the prevalence of indoor tanning over time. Random effects meta-analysis was used to summarize the prevalence of indoor tanning in adolescents and adults according to sex, region and presence of age prohibitions. RESULTS: Global prevalence of indoor tanning in adolescents for 2013-2018 was 6·5% [95% confidence interval (CI) 3·3-10·6], 70% lower than the 22·0% (95% CI 17·2-26·8) prevalence for 2007-2012. Among adults, the prevalence was 10·4% (95% CI 5·7-16·3) for 2013-2018, a decrease of 35% from 18·2% for 2007-2012. Since 2009, the overall past-year prevalence among adolescents was 6·7% (95% CI 4·4-9·6) and 12·5% (95% CI 9·5-15·6) among adults. The prevalence of tanning indoors in the past year was similar in North America (adults, 12·5%; adolescents, 7·6%) and Europe (adults, 11·1%; adolescents, 5·1%). In 2009, three countries had regulations restricting indoor tanning, compared with 26 countries today. CONCLUSIONS: Prevalence of indoor tanning has declined substantially and significantly in adolescents and adults since the 2009 IARC statement, reflecting the rise in regulations that limit this source of unnecessary exposure to carcinogenic ultraviolet radiation. What is already known about this topic? Indoor tanning is associated with an increased risk of melanoma. A meta-analysis of worldwide indoor tanning prevalence for 1986-2012 found a past-year prevalence of 18% in adolescents and 14% in adults, with higher prevalences during the period 2007-2012. Policies to regulate indoor tanning began to be implemented across the globe in 2009. Only one study carried out in the U.S.A. has evaluated the efficacy of such policies in reducing indoor tanning prevalence. What does this study add? For the period 2013-2018, we found indoor tanning prevalences of 6·7% in adolescents and 11·9% in adults. This implies a reduction in indoor tanning use of 70% in adolescents and 35% in adults during the last 10 years. Our study encourages policy makers to strengthen indoor tanning regulations that reduce sunbed use among the general population in order to produce maximum public health benefit.

Clinicopathological factors associated with death from thin (≤ 1·00 mm) melanoma.

BACKGROUND: Thin cutaneous melanomas (≤ 1·00 mm) are increasing worldwide, causing around a quarter of all melanoma deaths in the U.S.A. and Australia. Identification of predictive factors for potentially fatal thin melanomas could allow better use of resources for follow-up. OBJECTIVES: To identify the clinicopathological factors associated with fatal thin melanomas. METHODS: This large, nested case-case study extracted data from the population-based Queensland Cancer Registry, Australia. Our cohort consisted of Queensland residents aged 0-89 years who were diagnosed with a single, locally invasive thin melanoma (≤ 1·00 mm) between 1995 and 2014. Fatal cases (eligible patients who died from melanoma) were individually matched to three nonfatal cases (eligible patients who were not known to have died from melanoma) according to sex, age, year of diagnosis and follow-up interval. Using conditional logistic regression, we calculated odds ratios (ORs) for melanoma-specific death, adjusting for all collected clinicopathological variables. RESULTS: In the cohort, 27 660 eligible patients were diagnosed with a single, thin melanoma. The final case-case series included 424 fatal cases and 1189 nonfatal cases. Fatal cases were sixfold as likely to arise on the scalp as on the back [OR 6·39, 95% confidence interval (CI) 2·57-15·92] and six times as likely to be of thickness 0·80-1·00 mm as of < 0·30 mm (OR 6·00, 95% CI 3·55-10·17). CONCLUSIONS: Scalp location is a strong prognostic factor of death from thin melanoma. Further, this study provides support that melanomas with a thickness of 0·80-1·00 mm are the more hazardous thin lesions. Patients with these tumour characteristics require specific attention during follow-up. What's already known about this topic? Thin invasive melanomas (≤ 1·00 mm) contribute a substantial proportion of melanoma fatalities, owing to the high volume of disease. There is a need to find prognostic factors that will better identify fatal thin melanomas at the time of diagnosis. What does this study add? In this large population-based study, fatal thin tumours were sixfold as likely to be located on the scalp as on the back. Thin melanomas of 0·80-1·00 mm thickness were six times as likely to be associated with death as tumours < 0·30 mm. Scalp location and increasing thickness are strong predictive factors of fatal thin melanomas, indicating that patients with these tumour characteristics require close follow-up.

Skin cancer multiplicity in lung transplant recipients: a prospective population-based study.

BACKGROUND: Lung transplant recipients are at high risk of skin cancer, but precise annual incidence rates of treated skin cancers per patient are unknown. OBJECTIVES: To perform a prospective assessment of the total burden of histologically confirmed squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) and associated factors in lung transplant recipients. METHODS: A population-based cohort of 125 Queensland lung transplant recipients aged 18 years and over, recruited between 2013 and 2015, were followed to the end of 2016. All underwent dermatological skin examinations at baseline and annually thereafter and patients self-reported all interim treated skin cancers, which were verified against pathology databases. Standard skin cancer risk factors were obtained via questionnaire, and details of medications were acquired from hospital records. RESULTS: During a median follow-up time of 1·7 years, 29 (23%) and 30 (24%) lung transplant recipients with a median duration of immunosuppression of 3·3 years developed SCC and BCC, respectively. The general population age-standardized incidence rates of SCC and BCC were 201 and 171 per 1000 person-years, respectively (based on first primary SCC or BCC during follow-up); however, on accounting for multiple primary tumours, corresponding incidence rates were 447 and 281 per 1000 person-years. Risk of multiple SCCs increased around sixfold in those aged ≥ 60 years and in those with previous skin cancer, and increased around threefold in those treated with the antifungal medication voriconazole. Multiple BCC risk rose threefold from age 60 years and tenfold for patients with previous skin cancer. CONCLUSIONS: Lung transplant recipients have very high incidence of multiple primary skin cancers. Close surveillance and assiduous prevention measures are essential. Linked Comment: Proby and Harwood. Br J Dermatol 2020; 183:416-417.

Does polygenic risk influence associations between sun exposure and melanoma? A prospective cohort analysis.

BACKGROUND: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. However, data on these interactions from prospective studies are scant. OBJECTIVES: To quantify the association between ambient and personal ultraviolet exposure and incident melanoma in a large population-based prospective study of men and women residing in a setting of high ambient ultraviolet radiation, and to examine potential gene-environment interactions. METHODS: Data were obtained from the QSkin Sun and Health Study, a prospective cohort study of men and women aged 40-69 years, randomly sampled from the Queensland population in 2011. Participants were genotyped and assessed for ultraviolet exposure. RESULTS: Among participants with genetic data (n = 15 373), 420 (2·7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow-up time of 4·4 years. Country of birth, age at migration, having > 50 sunburns in childhood or adolescence, and a history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk. CONCLUSIONS: An interaction with polygenic risk was suggested: among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early-life ambient exposure (as measured by place of birth) were associated with melanoma (hazard ratio for born in Australia vs. overseas 3·16, 95% confidence interval 1·39-7·22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development. What's already known about this topic? The relationship between sun exposure and melanoma is complex, and exposure effects are highly modified by host factors and behaviours. The role of genotype on the relationship between ultraviolet radiation exposure and melanoma risk is poorly understood. What does this study add? We found that country of birth, age at migration, sunburns in childhood or adolescence, and history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk, while other measures of continuous or more intermittent patterns of sun exposure were not. We found evidence for gene-environment interactions that are consistent with divergent pathways for melanoma development. Linked Comment: Cust. Br J Dermatol 2020; 183:205-206. Plain language summary available online.