Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.

Predicting skin cancer in organ transplant recipients: development of the SUNTRAC screening tool using data from a multicenter cohort study.

Skin cancer is a common post-transplant complication. In this study, the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator (SUNTRAC) was developed to stratify patients into risk groups for post-transplant skin cancer. Data for this study were obtained from the Transplant Skin Cancer Network (TSCN), which conducted a multicenter study across 26 transplant centers in the United States. In total, 6340 patients, transplanted from 2003 and 2008, were included. Weighted point values were assigned for each risk factor based on beta coefficients from multivariable modeling: white race (9 points), pretransplant history of skin cancer (6 points), age ≥ 50 years (4 points), male sex (2 points), and thoracic transplant (1 point). Good prognostic discrimination (optimism-corrected c statistic of 0.74) occurred with a 4-tier system: 0-6 points indicating low risk, 7-13 points indicating medium risk, 14-17 points indicating high risk, and 18-22 points indicating very high risk. The 5-year cumulative incidence of development of skin cancer was 1.01%, 6.15%, 15.14%, and 44.75%, for Low, Medium, High, and Very High SUNTRAC categories, respectively. Based on the skin cancer risk in different groups, the authors propose skin cancer screening guidelines based on this risk model.

Clinical Features of Neutrophilic Dermatosis Variants Resembling Necrotizing Fasciitis.

Importance: Pyoderma gangrenosum and necrotizing Sweet syndrome are diagnostically challenging variants of neutrophilic dermatosis that can clinically mimic the cutaneous and systemic features of necrotizing fasciitis. Improved characterization of these rare variants is needed, as improper diagnosis may lead to inappropriate or delayed treatment and the potential for morbidity. Objective: To determine the characteristics of necrotizing neutrophilic dermatosis to improve diagnostic accuracy and distinguish from infection. Design, Setting, and Participants: A case series of patients with necrotizing neutrophilic dermatosis treated at 3 academic hospitals (University of California San Francisco, Oregon Health and Science University, and University of Minnesota) from January 1, 2015, to December 31, 2017, was performed along with a literature review of related articles published between January 1, 1980, and December 31, 2017. Data were obtained from medical records as well as Medline and Embase databases. All patients had signs resembling necrotizing infection and had a final diagnosis of pyoderma gangrenosum with systemic features or necrotizing Sweet syndrome. Patients were excluded if a diagnosis other than neutrophilic dermatosis was made, if key clinical information was missing, and if reported in a non-English language. Main Outcomes and Measures: Description of key characteristics of necrotizing neutrophilic dermatosis. Results: Overall, 54 patients with necrotizing neutrophilic dermatosis were included, of which 40 had pyoderma gangrenosum with systemic features and 14 had necrotizing Sweet syndrome. Of the 54 patients, 29 (54%) were male and 25 (46%) were female, with a mean (SD) age of 51 (19) years. Skin lesions commonly occurred on the lower (19 [35%]) and upper (13 [24%]) extremities and developed after a surgical procedure (22 [41%]) or skin trauma (10 [19%]). Shock was reported in 14 patients (26%), and leukemoid reaction was seen in 15 patients (28%). Of the patients with necrotizing neutrophilic dermatosis, 51 (94%) were initially misdiagnosed as necrotizing fasciitis and subsequently received inappropriate treatment. Debridement was performed in 42 patients (78%), with a mean (SD) of 2 (2 [range, 1-12]) debridements per patient. Four amputations (7%) were performed. Forty-nine patients (91%) received antibiotics when necrotizing neutrophilic dermatosis was misdiagnosed as an infection, and 50 patients (93%) received systemic corticosteroids; all patients responded to immunosuppressants. Conclusions and Relevance: A complex spectrum of clinical findings of pyoderma gangrenosum and Sweet syndrome with prominent systemic inflammation exists that defines a new subset of neutrophilic dermatoses, termed necrotizing neutrophilic dermatoses; recognizing the difference between this variant and severe infection may prevent unnecessary surgical procedures and prolonged disease morbidity associated with a misdiagnosis and may expedite appropriate medical management.

Incidence of and Risk Factors for Skin Cancer in Organ Transplant Recipients in the United States.

Importance: Skin cancer is the most common malignancy occurring after organ transplantation. Although previous research has reported an increased risk of skin cancer in solid organ transplant recipients (OTRs), no study has estimated the posttransplant population-based incidence in the United States. Objective: To determine the incidence and evaluate the risk factors for posttransplant skin cancer, including squamous cell carcinoma (SCC), melanoma (MM), and Merkel cell carcinoma (MCC) in a cohort of US OTRs receiving a primary organ transplant in 2003 or 2008. Design, Setting, and Participants: This multicenter retrospective cohort study examined 10 649 adult recipients of a primary transplant performed at 26 centers across the United States in the Transplant Skin Cancer Network during 1 of 2 calendar years (either 2003 or 2008) identified through the Organ Procurement and Transplantation Network (OPTN) database. Recipients of all organs except intestine were included, and the follow-up periods were 5 and 10 years. Main Outcomes and Measures: Incident skin cancer was determined through detailed medical record review. Data on predictors were obtained from the OPTN database. The incidence rates for posttransplant skin cancer overall and for SCC, MM, and MCC were calculated per 100 000 person-years. Potential risk factors for posttransplant skin cancer were tested using multivariate Cox regression analysis to yield adjusted hazard ratios (HR). Results: Overall, 10 649 organ transplant recipients (mean [SD] age, 51 [12] years; 3873 women [36%] and 6776 men [64%]) contributed 59 923 years of follow-up. The incidence rates for posttransplant skin cancer was 1437 per 100 000 person-years. Specific subtype rates for SCC, MM, and MCC were 812, 75, and 2 per 100 000 person-years, respectively. Statistically significant risk factors for posttransplant skin cancer included pretransplant skin cancer (HR, 4.69; 95% CI, 3.26-6.73), male sex (HR, 1.56; 95% CI, 1.34-1.81), white race (HR, 9.04; 95% CI, 6.20-13.18), age at transplant 50 years or older (HR, 2.77; 95% CI, 2.20-3.48), and being transplanted in 2008 vs 2003 (HR, 1.53; 95% CI, 1.22-1.94). Conclusions and Relevance: Posttransplant skin cancer is common, with elevated risk imparted by increased age, white race, male sex, and thoracic organ transplantation. A temporal cohort effect was present. Understanding the risk factors and trends in posttransplant skin cancer is fundamental to targeted screening and prevention in this population.

Trends of skin cancer mortality after transplantation in the United States: 1987 to 2013.

BACKGROUND: Solid organ transplant recipients are at increased risk of skin cancer, but population-based mortality data are limited. OBJECTIVE: Mortality and predictors of skin cancer death posttransplantation were investigated. METHODS: All US organ transplant recipients between 1987 and 2013, identified through the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research file, were included. Mortality and hazard ratios (HR) were calculated for the overall population and patient subgroups. RESULTS: The overall mortality was 5308 per 100,000 person-years and the skin cancer-specific mortality was 35.27 per 100,000 person-years. Risk factors associated with skin cancer death included thoracic versus abdominal transplantation (HR 2.90, 95% confidence interval [CI] 2.52-3.34), age over 50 years (HR 2.86, CI 2.43-3.38), white race (HR 6.29, CI 4.63-8.53), and male sex (HR 1.85, CI 1.57-2.19). Mortality was highest for malignant melanoma (mortality of 11.48), followed by squamous cell carcinoma (mortality of 4.94) and Merkel cell carcinoma (mortality of 4.59). LIMITATIONS: Limitations of this study included potential underreporting and misclassification of death from skin cancer in the data set. CONCLUSION: Mortality from posttransplantation skin cancer is reported. Older patients, male patients, white patients, and thoracic transplant recipients had increased mortality from skin cancer.

Canonical/ß-catenin Wnt pathway activation improves retinal pigmented epithelium derivation from human embryonic stem cells.

PURPOSE: The purpose of this study was to better understand the role canonical/ß-catenin Wnt signaling plays in the differentiation of human embryonic stem cells (hESCs) into retinal pigmented epithelium (RPE), with the goal of improving methods for derivation. METHODS: Fluorescent reporters were generated to monitor RPE differentiating from hESCs by using a previously described 14-day derivation protocol. Reporters were used to test the effects of the canonical/ß-catenin Wnt pathway agonist CHIR99021 on differentiating RPE. Cells derived from differentiation studies were characterized by lineage-specific transcription factor expression, morphology, pigmentation, and function. The RPE derivation efficiency was determined from percentage positive PMEL17 expression. RESULTS: Fluorescent reporters mimicked expression of endogenous genes during 14-day differentiation to RPE. Analysis of Wnt pathway gene expression showed that the pathway components are expressed in differentiating RPE cells. Addition of CHIR99021 improved RPE derivation based on morphology, expression of RPE-specific lineage markers, and genes involved in melanogenesis. Additionally, expression of the neural retina marker CHX10 was suppressed during differentiation with CHIR99021. Addition of soluble WNT3A, but not WNT5A, had the same result. The CHIR99021-modified protocol yielded cell populations that were 97.77% ± 0.1% positive for the RPE marker PMEL17 at day 14. After cells were expanded to passage 3, they were shown to express RPE markers, carry out phagocytosis of rod outer segments, and secrete pigment epithelium-derived factor apically and vascular endothelial growth factor basally. CONCLUSIONS: Our findings demonstrated the importance of canonical/ß-catenin Wnt signaling in RPE differentiation and showed that manipulating the pathway significantly improves RPE derivation from hESC.