The Role of Sex and Gender in Dermatology - From Pathogenesis to Clinical Implications.

BACKGROUND: Sex and gender have increasingly been recognized as significant risk factors for many diseases, including dermatological conditions. Historically, sex and gender have often been grouped together as a single risk factor in the scientific literature. However, both may have a distinct impact on disease incidence, prevalence, clinical presentation, severity, therapeutic response, and associated psychological distress. OBJECTIVES AND PROJECT DESCRIPTION: The mechanisms that underlie differences in skin diseases between males, females, men, and women remain largely unknown. The specific objectives of this review paper are:To highlight the biological differences between males and females (sex), as well as the sociocultural differences between men and women (gender) and how they impact the integumentary system.To perform a literature review to identify important sex- and gender-related epidemiological and clinical differences for various skin conditions belonging to a range of disease categories and to discuss possible biological and sociocultural factors that could explain the observed differences.To discuss dermatological skin conditions and gender-affirming treatments within the transgender community, a population of individuals who have a gender identity which is different than the gender identity they were assigned at birth. FUTURE IMPACT: With the rising number of individuals that identify as non-binary or transgender within our increasingly diverse communities, it is imperative to recognize gender identity, gender, and sex as distinct entities. By doing so, clinicians will be able to better risk-stratify their patients and select treatments that are most aligned with their values. To our knowledge, very few studies have separated sex and gender as two distinct risk factors within the dermatology literature. Our article also has the potential to help guide future prevention strategies that are patient-tailored rather than using a universal approach.

Penile Invasive Squamous Cell Carcinoma: Analysis of Incidence, Mortality Trends, and Geographic Distribution in Canada.

BACKGROUND: Penile invasive squamous cell carcinoma (SCC) is a rare disease with several known risk factors. However, few studies have assessed its incidence, mortality, and temporal trends. OBJECTIVE: Our objectives are to analyze the epidemiology of penile SCC in Canada and to examine patient distribution with this cancer across Canada in order to elucidate population risk factors. METHODS: Three independent cancer registries were used to retrospectively analyze demographic data from Canadian men diagnosed with penile invasive SCC between 1992 and 2010. The Canadian Census of Population was used to calculate incidence and mortality rates at the province and Forward Sortation Area levels. RESULTS: The overall age-adjusted incidence rate was 6.08 cases per million males. Four provinces with statistically significantly higher incidence rates were identified. The national crude incidence rates increased linearly between 1992 and 2010, whereas the age-adjusted incidence rates showed no significant increase during this time period. The overall age-adjusted mortality rate was 1.88 deaths per million males per year. The province of Saskatchewan had significantly higher mortality rates. There was no increase in crude or age-adjusted mortality rates between 1992 and 2010. There was a significant positive correlation between incidence rates and obesity, Caucasian ethnicity, and lower socioeconomic status. CONCLUSION: This study was able to establish geographic variation for this malignancy at the provincial level. Although there are many established risk factors for penile SCC, our results suggest that the increase in crude incidence rates observed is largely due to the aging population.

Analysis of acute myeloid leukemia incidence and geographic distribution in Canada from 1992 to 2010 reveals disease clusters in Sarnia and other industrial US border cities in Ontario.

BACKGROUND: Several risk factors have been implicated in acute myeloid leukemia (AML) leukemogenesis. However, the epidemiologic distribution and precise triggers for AML in Canada remain poorly understood. METHODS: In this study, demographic data for AML patients in Canada from 1992 to 2010 were analyzed using 3 independent population-based cancer registries. The AML incidence and mortality rates were examined at the levels of province/territory, city, and forward sortation area (FSA) postal code. RESULTS: In total, 18,085 patients were identified. AML incidence was documented to be 30.61 cases per million individuals per year (95% confidence interval [CI], 30.17-31.06) from 1992 to 2010. Five industrial cities in Ontario were identified where incidence rates were significantly higher than the national average: Sarnia, Sault Ste. Marie, Thunder Bay, St. Catharines, and Hamilton. Analysis at the FSA postal code level identified significant patient clusters of AML in these cities. Specifically, FSA N7V in Sarnia, Ontario had an incidence of 106.81 (95% CI, 70.96-161.86) cases per million individuals per year, which is >3 times higher than the national average. The pollution from local oil refineries and chemical plants in Sarnia may be implicated as a risk factor for AML in that city. Analysis of mortality rates at the province and city levels corroborated the findings from the incidence data. CONCLUSION: These results provide a comprehensive analysis of AML burden in Canada and reveal striking geographic case clustering in industrial Ontario cities and potentially implicate exposure to materials/pollution from these plants as an important risk factor for developing AML in Canada.

Multiple myeloma epidemiology and patient geographic distribution in Canada: A population study.

BACKGROUND: Multiple myeloma (MM) is a malignancy of mature plasma cells. Environmental risk factors identified for this malignancy, among others, include farming and exposure to pesticides. METHODS: Using 3 independent population-based databases (the Canadian Cancer Registry, le Registre Québécois du Cancer, and Canadian Vital Statistics), this study analyzed patients' clinical characteristics and the incidence, mortality, and geographic distribution of MM cases in Canada during 1992-2015. RESULTS: In total, ~32,065 patients were identified, and 53.7% were male. The mean age at the time of diagnosis was 70 ± 12.1 years. The average incidence rate in Canada was 54.29 cases per million individuals per year, and linear regression modeling showed a steady rise in the annual rate of 0.96 cases per million individuals per year. At the provincial level, Quebec and Ontario had significantly higher incidence rates than the rest of Canada. An analysis of individual municipalities and postal codes showed lower incidence rates in large metropolitan areas and in high-latitude regions of the country, whereas high incidence rates were observed in smaller municipalities and rural areas. Land use analysis demonstrated increased density of crop farms and agricultural industries in high-incidence areas. A comparison with the available data from 2011-2015 showed several consistent trends at provincial, municipal, and regional levels. CONCLUSIONS: These results provide a comprehensive analysis of the MM burden in Canada. Large metropolitan cities as well as high-latitude regions were associated with lower MM incidence. Higher incidence rates were noted in smaller cities and rural areas and were associated with increased density of agricultural facilities.

Analysis of incidence, mortality trends, and geographic distribution of breast cancer patients in Canada.

BACKGROUND/PURPOSE: Breast cancer is the malignancy with the highest incidence rate excluding non-melanoma skin cancers, and the second leading cause of cancer-related deaths among Canadian women. Many modifiable risk factors have been linked to the pathogenesis of this disease. The purpose of this study is to analyze the epidemiology of breast cancer in Canada and to examine its geographic distribution to help identify new risk factors for this disease. METHODS: Three independent population-based cancer registries were used to retrospectively analyze demographic data from Canadian women diagnosed with invasive breast cancer across all provinces and territories between 1992 and 2010. The incidence and mortality rates were assessed at the provincial, city, and forward sortation area (FSA) postal code levels. RESULTS: The overall age-adjusted incidence rate was 114.4 cases per 100,000 females per year. Six provinces and several groups of FSAs had significantly higher incidence rates. There was a significant increase in incidence and decrease in mortality rates between 1992 and 2010. The overall mortality rate was 31.5 deaths per 100,000 females per year. However, three provinces had significantly higher mortality rates. CONCLUSION: By identifying high-incidence areas for breast cancer, our study will help identify patient populations that are at higher risk for this malignancy. It will also act as a foundation for future studies to establish novel risk factors for this disease.

Cutaneous malignant melanoma incidence and mortality trends in Canada: A comprehensive population-based study.

BACKGROUND: The incidence of cutaneous malignant melanoma (CMM) is on the rise in many parts of the world. However, there is limited knowledge on the epidemiology of CMM in Canada. OBJECTIVE: To conduct a comprehensive population-based study of CMM in Canada. METHODS: We examined patient clinical and pathologic characteristics as well as the incidence and mortality trends of CMM in Canada using 3 independent population-based registries. RESULTS: In total, 72,565 Canadian patients were given CMM diagnoses during 1992-2010; 47.5% were women. Average age at the time of diagnosis was 56.5 years for women and 60.4 years for men. We report a steady increase in CMM incidence and mortality rates in both sexes. The overall incidence rate of CMM in Canada was 12.29 cases/100,000 person-years. We also report important differences in the incidence and mortality rates between Canadian provinces and territories; the highest incidence of this cancer was documented in Nova Scotia and Prince Edward Island. LIMITATIONS: Data on race, clinical disease stage, and Breslow depth of CMM was not available. CONCLUSION: This study, for the first time, defines the disease burden of CMM in Canada and highlights important longitudinal, geographic, and spatial differences in the distribution of CMM in this country.

Distribution and Clustering of Cutaneous T-Cell Lymphoma (CTCL) Cases in Canada During 1992 to 2010.

BACKGROUND: Clustering of patients with cutaneous T-cell lymphoma (CTCL) was reported in several jurisdictions around the world. This rare cancer is known to affect spouses and in some cases multiple members of the same family. These combined results suggest the existence of external disease triggers/promoters. We recently conducted the first comprehensive analysis of CTCL incidence and mortality in Canada, which revealed case clustering in several regions. OBJECTIVES: To extend our previous analysis on CTCL incidence across Canada and to provide all the collected data on CTCL patient incidence in Canada during the period of 1992 to 2010. METHODS: Clinical parameters for patients with CTCL in Canada were analyzed using 2 independent population-based cancer registries: Canadian Cancer Registry and Le Registre Québécois du Cancer. The CTCL incidence rates were examined on different geographical levels, including provinces/territories, cities, and forward sortation areas. RESULTS: Our findings further corroborate our earlier observations of higher CTCL incidence in Newfoundland and Labrador, maritime provinces (Nova Scotia and New Brunswick), and prairie provinces (Manitoba and Saskatchewan). Also, most cities with high CTCL incidence were located in these provinces. Extensive mapping of high-incidence postal codes supports case clustering in a number of communities that are located in the proximity of industrial centres and seaports. CONCLUSIONS: Detailed analysis of CTCL incidence in Canada is critical to fully understand the burden of this disease in our country, to begin the search for a possible external trigger for this lymphoma, and to reform how health care resources are distributed throughout the country to better serve Canadian patients with CTCL.

Comprehensive analysis of cutaneous T-cell lymphoma (CTCL) incidence and mortality in Canada reveals changing trends and geographic clustering for this malignancy.

BACKGROUND: Previous reports of geographic clustering of cutaneous T-cell lymphoma (CTCL) in Texas, Pittsburgh, and Sweden as well as the occurrence of CTCL in married couples and family members raise a possibility of the existence of an external and potentially preventable trigger(s) for this rare skin cancer. METHODS: The authors studied CTCL incidence and mortality in Canada using 3 distinct population-based cancer databases. Data on patients' sex, age at the time of diagnosis, subtype of CTCL malignancy, reporting province, city, and postal code were analyzed. CTCL cases were mapped across Canada using geographic information systems software. RESULTS: In total, 6685 patients with CTCL were identified in Canada during 1992 through 2010 (CTCL incidence rate, 11.32 cases per million individuals per year), of which 58% were males. The mean age at diagnosis was 59.4 ± 21.5 years. Geographic analysis of patients revealed increased CTCL incidence on the provincial and city levels in several eastern provinces and in Manitoba. An analysis according to postal codes (Forward Sortation Area [FSA]) identified select communities in which several high-incidence FSAs were contiguous or adjacent. Several of these FSAs were located in industrial regions of Canadian cities. Conversely, 3 of 8 low-incidence FSAs were clustered in Ottawa, Ontario, which has very little industrial presence. An analysis of CTCL mortality in Canada corroborated the current incidence findings. CONCLUSIONS: The current results provide a comprehensive analysis of CTCL burden in Canada and highlight several important areas of geographic case clustering. These findings argue that industrial exposures may play an important role in promoting CTCL pathogenesis. Cancer 2017;123:3550-67. © 2017 American Cancer Society.

Positive CD63 Basophil Activation Tests Are Common in Children with Chronic Spontaneous Urticaria and Linked to High Disease Activity.

BACKGROUND: The basophil activation test (BAT) using CD63 expression is a sensitive and specific tool for the diagnostic workup of autoimmune chronic spontaneous urticaria (CSU). The definition of a positive BAT is directly dependent on the reference range and the cutoff values established in control populations. As of now, the pediatric reference range and cutoff values of the CD63 BAT remain to be established. METHODS: In this study, we analyzed CD63 expression in 80 children (1-17 years old) without chronic urticaria (i.e., controls) and compared the values to those of a pediatric cohort of 105 CSU patients and 23 physical urticaria (PU) patients. RESULTS: Based on the log-normal distribution of CD63 values in control subjects, the reference range and the cutoff for positive CD63 BAT values was established to be 1.2-1.8% (95% CI) and 1.8%, respectively. Children with CSU showed significantly elevated and significantly increased BAT values compared to healthy controls (Wilcoxon rank test p value <0.001). In contrast, no difference was found between BAT results in controls and PU patients. In pediatric CSU patients, a higher disease activity was associated with higher BAT values. CONCLUSIONS: Our study provides, for the first time, reference and cutoff values for the CD63 BAT in children. Our findings show that positive CD63 BAT are common in children with CSU and linked to a high disease activity.

Eruptive disseminated pyogenic granulomas following lightning injury.

BACKGROUND: Pyogenic granuloma (PG) is a common benign acquired vascular tumor. It classically presents as a solitary friable nodule on the face or distal extremities. Disseminated eruption is rare and can occur spontaneously or secondary to various triggers, including burn injury. To date, the literature reports only 13 cases of eruptive PGs following burn injury, most from exposure to boiling milk or water. We report the first case of disseminated eruptive PGs following a lightning injury. CASE: A 17-year-old previously healthy boy developed second- and third-degree burns following lightning injury. Two weeks later, he developed widespread dark-purple polypoid exophytic tumors ranging from 1 to 10 cm in diameter extending beyond the limits of the initial burn injury. The lesions were friable and often formed erosions and crusts. The patient was otherwise well and laboratory and microbiological investigations were normal. Excisional biopsy of a lesion was diagnostic of PG and the patient was treated with surgical excision of the lesions, without recurrence. CONCLUSION: The exact pathogenesis of multiple PGs remains unknown. Several pathogenic mechanisms have been suggested, including production of angiogenic factors that stimulate endothelial proliferation and formation of minute arteriovenous fistulas by trauma.

Measuring h-index and scholarly productivity in academic dermatology in Canada.

Promotion in academia heavily relies on research productivity. The h-index is a standardized metric used to quantify research productivity at the individual level. We evaluated factors associated with h -index in dermatology across select Canadian academic centers with special focus on sex and academic rank. Medical academic centers throughout Canada with dermatology training programs were included. For each faculty member, we extracted the following data from public sources: sex, graduate degree, academic rank, years since the Fellow of the Royal College of Physicians and Surgeons of Canada (FRCPC) certification or equivalent, recent Canadian Institutes of Health Research (CIHR) funding and H-index (based on Scopus author profile). Log-linear univariate and multivariate regression analyses were performed to evaluate the association between h-index and these factors. An ordinal logistic regression was performed to explore sex differences in academic ranking. Our results showed that out of 300 faculty members across Canada, 155 were females (51.67%) and 145 were male (48.33%). H-index was available for 279 dermatologists. The average h-index was 8.35 (SD 11.53) and the median was 4.00 (1st quartile = 2.00, 3rd quartile = 10.00). Higher h-index was associated with more years since dermatology certification, successive academic rank, graduate degree and recent CIHR funding, but not with sex. In conclusion, h-index was not associated with sex when controlling for potential confounders. These results could reflect recent demographic changes in the field with an increase in newly appointed female dermatologists. Longitudinal assessment of academic productivity in dermatology is needed to assess the impact of continued efforts to promote equal opportunities in the field.

Incidence and Mortality of Prostate Cancer in Canada during 1992-2010.

In Canada, prostate cancer is the most common reportable malignancy in men. We assessed the temporal trends of prostate cancer to gain insight into the geographic incidence and mortality trends of this disease. Three independent population-based cancer registries were used to retrospectively analyze demographic data on Canadian men diagnosed with prostate cancer and men who died of prostate cancer between the years of 1992 and 2010. The incidence and mortality rates were calculated at the provincial, city, and forward sortation area (FSA) postal code levels by using population counts that were obtained from the Canadian Census of Population. The Canadian average incidence rate was 113.57 cases per 100,000 males. There has been an overall increasing trend in crude prostate cancer incidence between 1992 and 2010 with three peaks, in 1993, 2001, and 2007. However, age-adjusted incidence rates showed no significant increase over time. The national mortality rate was calculated to be 24.13 deaths per 100,000 males per year. A decrease was noted in crude and age-adjusted mortality rates between 1992 and 2010. Several provinces, cities, and FSAs had higher incidence/mortality rates than the national average. Several of the FSA postal codes with the highest incidence/mortality rates were adjacent to one another. Several Canadian regions of high incidence for prostate cancer have been identified through this study and temporal trends are consistent with those reported in the literature. These results will serve as a foundation for future studies that will seek to identify new regional risk factors and etiologic agents.

Epidemiology of ophthalmic lymphoma in Canada during 1992-2010.

BACKGROUND: Ophthalmic lymphoma (OL) is the most common orbital tumour, particularly in older individuals. Little is known about the epidemiology and geographic distribution of OL in Canada. Descriptive demographic statistics are an important first step in understanding OL burden and are necessary to inform comprehensive national cancer prevention programmes. METHODS: We determined patterns of incidence and geographical distribution of the three major subtypes of OL: extranodal marginal zone B cell lymphoma, follicular lymphoma (FL) and diffuse large B cell lymphoma. Here, we used cases that were diagnosed during 1992-2010 using two independent population-based cancer registries, the Canadian Cancer Registry and Le Registre Québécois du Cancer (LRQC). RESULTS: The OL mean annual age-standardised incidence rate for 1992-2010 was 0.65 cases per million people per year with an average annual increase in the incidence rate of 4.5% per year. The mean age of diagnosis was 65 years. OL incidence rate was the highest in the cities located along the heavily industrialised Strait of Georgia in British Columbia. CONCLUSIONS: Our data on patient age, sex and temporal trends showed similarities with data reported in the USA and Denmark. Additional studies are needed to determine whether the observed increase in OL incidence is genuine or spurious.

Epidemiology of invasive ocular surface squamous neoplasia in Canada during 1992-2010.

BACKGROUND: Ocular surface squamous neoplasia (OSSN) is the most common non-pigmented ocular surface malignancy. It is classified as invasive OSNN (IOSSN) when the underlying stroma are infiltrated by dysplastic squamous epithelial cells through the basement membrane. Here, we present the descriptive epidemiology and geographical distribution of IOSSN in Canada. METHODS: We determined the incidence and geographical distribution of IOSSN cases diagnosed between 1992 and 2010 using two independent population-based cancer registries: the Canadian Cancer Registry and Le Registre Québécois du Cancer. RESULTS: The mean annual age-standardised incidence rate (WHO 2000-2025) of IOSSN for 1992-2010 was 0.45 cases per million individuals per year with an average annual percent increase in incidence of 4.5%. IOSSN localisation to the conjunctiva was documented in at least 57% of the reported cases. IOSSN exhibited a male predilection ratio of 3.3:1.0 with a mean age at diagnosis of 69 years. Incidence rates of IOSSN across Canadian provinces and cities showed no significant differences from the crude national average. CONCLUSIONS: Our results, particularly concerning IOSSN patient age and male predilection, corroborate with data reported from the USA. Additional studies are needed to determine whether the observed increase in incidence rate over the study period (1992-2010) is significant.

Uveal melanoma incidence trends in Canada: a national comprehensive population-based study.

BACKGROUND: In the developed countries, uveal melanoma is the most common primary intraocular malignancy in adults. Little is known about the epidemiological and geographical distribution of uveal melanoma in Canada. METHODS: To determine the incidence patterns and geographical distribution of uveal melanoma cases in Canada, we conducted the first comprehensive, population-based national study of this malignancy across all Canadian provinces and territories during 1992-2010 years. We examined two independent population-based registries: the Canadian Cancer Registry and Le Registre Québécois du Cancer using corresponding International Classification of Diseases for Oncology-3rd edition codes for all histological subtypes of uveal melanoma. RESULTS: We report that 2215 patients were diagnosed with uveal melanoma, of which 52.1% were males. The average -annual incidence rate of uveal melanoma in Canada was 3.75 cases per million individuals per year (95% CI 3.60 to 3.91). Overall, we report a steady increase in uveal melanoma incidence with an annual increase of 0.074 cases per million individuals per year. Significant differences in the incidence rates of uveal melanoma between Canadian provinces and territories were noted, where the highest crude incidence was in British Columbia and Saskatchewan with rates of 6.38 and 5.47 cases per million individuals per year, respectively. CONCLUSIONS: This work, for the first time, defines the disease burden of uveal melanoma in Canada and highlights important longitudinal, geographical and spatial differences in the distribution of uveal melanoma in Canada.

Occupational Contact Dermatitis in the Canadian Aircraft Industry.

BACKGROUND: Aircraft building exposes workers to irritant and sensitizing products. OBJECTIVE: The aim of this article was to study occupational dermatoses among aircraft workers over 25 years. METHODS: The files of aerospace workers referred between 1990 and 2015 were extracted from the database of the McGill University Health Centre contact dermatitis clinic. These were subdivided according to demographics, type of work, patch testing results, and final diagnosis. RESULTS: Of 305 workers, 58% were 40 years or younger; one third were women. Onset of dermatitis varied from 2 months to 25 years, but 120 cases (39%) occurred during the first 3 years. Fifty-one percent of the cases involved assemblers, and 27% were composite material technicians, which were overrepresented as they constitute 10% of the workforce. Of the 305 workers, 152 suffered from allergic contact dermatitis, and 96 had irritant contact dermatitis. Of those with allergic contact dermatitis, 124 reacted to epoxy-based workplace products, but only 48 had positive patch tests to commercially available epoxy allergens. CONCLUSION: More than 60% of the cases of epoxy allergy would have been missed without testing with workplace products.

A study of meiomitosis and novel pathways of genomic instability in cutaneous T-cell lymphomas (CTCL).

Genomic instability is a hallmark of cancer and an enabling factor for genetic alterations that drive cancer development and progression. The clashing of mitosis and aberrantly expressed meiosis machineries, which may contribute to genomic instability, has been coined cancer "meiomitosis". LINE-1 retrotransposition, a process active in germ cells, acts outside of the meiotic machinery to create DNA double strand breaks (DNA DSBs) and has played an important role in the evolution of the human genome. We have previously demonstrated that in CTCL several cancer testis/meiotic genes are expressed. Furthermore, this cancer exhibits extensive and ongoing chromosomal/microsatellite instability. In this study we analyzed immortalized patient-derived cells and primary CTCL patient samples using RT-PCR, western blotting and confocal microscopy and found that proteins critically involved in meiosis and LINE-1 retrotransposition are expressed and are associated with chromosomal instability and DNA DSB formation. Using cell cycle synchronization, we show G1/S phase-transition-specific expression of meiosis proteins. Using the Alu retrotransposition assay, we demonstrate the functional activity of LINE-1 retrotransposon in CTCL. Histone acetyltransferase inhibition results in downregulation of the ectopic germ cell programs and concomitant decrease in DNA DSBs foci formation. Notably, LINE-1 and meiosis genes were expressed across a panel of other solid tumor cell lines. Taken together, our results indicate that malignant cells in culture undergo "cancer meiomitosis" rather than the classic mitosis division. The ectopic expression of meiosis genes and reactivation of LINE-1 may be contributing to genomic instability and represent novel targets for immunotherapy in this and other cancers.