Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. METHODS: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. RESULTS: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%). CONCLUSIONS: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Skin Cancer Development in Solid Organ Transplant Recipients in Switzerland (Swiss Transplant Cohort Study).

IMPORTANCE: Skin cancer, in particular squamous cell carcinoma, is the most frequent malignancy among solid organ transplant recipients with a higher incidence compared to the general population. OBJECTIVE: To determine the skin cancer incidence in organ transplant recipients in Switzerland and to assess the impact of immunosuppressants and other risk factors. DESIGN: Prospective cohort study of solid organ transplant recipients in Switzerland enrolled in the Swiss Transplant Cohort Study from 2008 to 2013. PARTICIPANTS: 2,192 solid organ transplant recipients. MATERIALS AND METHODS: Occurrence of first and subsequent squamous cell carcinoma, basal cell carcinoma, melanoma and other skin cancers after transplantation extracted from the Swiss Transplant Cohort Study database and validated by medical record review. Incidence rates were calculated for skin cancer overall and subgroups. The effect of risk factors on the occurrence of first skin cancer and recurrent skin cancer was calculated by the Cox proportional hazard model. RESULTS: In 2,192 organ transplant recipients, 136 (6.2%) developed 335 cases of skin cancer during a median follow-up of 32.4 months, with squamous cell carcinoma as the most frequent one. 79.4% of skin cancer patients were male. Risk factors for first and recurrent skin cancer were age at transplantation, male sex, skin cancer before transplantation and previous transplantation. For a first skin cancer, the number of immunosuppressive drugs was a risk factor as well. CONCLUSIONS AND RELEVANCE: Skin cancer following solid organ transplantation in Switzerland is greatly increased with risk factors: age at transplantation, male sex, skin cancer before transplantation, previous transplantation and number of immunosuppressive drugs.

A step-wise approach for establishing a multidisciplinary team for the management of tuberous sclerosis complex: a Delphi consensus report.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder associated with mutations in TSC1 and TSC2 genes, upregulation of mammalian target of rapamycin signaling, and subsequent tumor formation in various organs. Due to the many manifestations of TSC and their potential complications, management requires the expertise of multiple medical disciplines. A multidisciplinary care approach is recommended by consensus guidelines. Use of multidisciplinary teams (MDTs) has been shown to be beneficial in treating other complex diseases, such as cancer. In a lifelong disease such as TSC, an MDT may facilitate the transition from pediatric to adult care. However, little guidance exists in the literature regarding how to organize an MDT in TSC. METHODS: To discuss the best approach to assembling an MDT, this project was initiated in October 2017 with a meeting of 12 physicians from various specialties and various countries. Following this first meeting, the experts generated statements on the most important aspects to implement in establishing an MDT for TSC by 3 rounds of selection using a Delphi process via electronic correspondence. Finally, TSC patient advocates reviewed the findings and provided additional insights from a patient perspective. RESULTS: A 3-step roadmap was recommended, starting with identifying a single individual to begin organizing care (Step 1), then establishing a small core team (Step 2), and finally, establishing a larger multi-disciplinary team (Step 3). Because of the multisystemic nature of TSC, the MDT should include specialists such as a neurologist, a neurosurgeon, a nephrologist, a urologist, a pulmonologist, an ophthalmologist, a cardiologist, a dermatologist, a geneticist, and a psychiatrist/psychologist. The MDT should recommend a care plan for each patient based on the individual's needs and in consultation with him/her or his/her family. Some of the most important aspects of an MDT that were agreed upon included identifying a case manager to help coordinate care, providing access to health care professionals of varying specialties, and including a lead physician who takes medical responsibility for patients' overall care. CONCLUSIONS: The results of our consensus provide guidance to support the initiation of an MDT in TSC.

Prevalence of Actinic Keratosis in Patients Attending General Practitioners in Switzerland.

BACKGROUND: Most of the data concerning the prevalence of actinic keratosis (AK) originate from the USA and Australia, and recently from Austria and Spain, but are based on populations in dermatology practices. Switzerland is the leading country with skin cancer incidence in Europe. AK prevalence among the Swiss population is therefore an important public health issue. OBJECTIVE: To assess the prevalence of AK in the outpatient Swiss population in general practice. METHODS: General practitioners captured AK diagnosis stage and localization in consecutive patients, who attended the physician for any reason. RESULTS: A total of 2,844 consecutive patients (55.7% female) were enrolled in 59 general practitioners' offices. AK prevalence was 25.3% and increased steadily with age; 33% of men and 19% of women were diagnosed with AK. Every second AK patient declared leisure-related UV exposure, while only 23% were exposed to UV occupationally; 16% of the patients were UV exposed both occupationally and during leisure. AK distribution among sun-exposed body sites and extent of disease varied by sex. CONCLUSION: In Switzerland AK is a common diagnosis in dermatology practices. Since up to 5% of AK may progress to invasive squamous cell carcinoma (SCC), prevention of AK, as well as education of patients and general practitioners, may play a critical role for subsequent SCC development. This is the first study on AK prevalence in Switzerland identifying patients most affected by AK. These results will help to define future approaches to target general practitioners for education, screening, and specific intervention in patients with AK.

Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results.

Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor-based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.

The ARE-binding protein Tristetraprolin (TTP) is a novel target and mediator of calcineurin tumor suppressing function in the skin.

An increased incidence of skin inflammatory diseases is frequently observed in organtransplanted patients being treated with calcineurin inhibitor-based immunosuppressive agents. The mechanism of increased skin inflammation in this context has however not yet been clarified. Here we report an increased inflammation following inhibition of calcineurin signaling seen in both chemically induced mouse skin tumors and in tumors grafted from H-rasV12 expressing primary human keratinocytes (HKCs). Following UVB or TPA treatment, we specifically found that deletion of the calcineurin gene in mouse keratinocytes (MKCs) resulted in increased inflammation, and this was accompanied by the enhanced production of pro-inflammatory cytokines, such as TNFα, IL-8 and CXCL1. Furthermore, expression of the RNA-binding protein, tristetraprolin (TTP) was down-regulated in response to calcineurin inhibition, wherein TTP was shown to negatively regulate the production of pro-inflammatory cytokines in keratinocytes. The induction of TTP following TPA or UVB treatment was attenuated by calcineurin inhibition in keratinocytes, and correspondingly, disruption of calcineurin signaling down-regulated the amounts of TTP in both clinical and H-rasV12-transformed keratinocyte tumor models. Our results further demonstrated that calcineurin positively controls the stabilization of TTP in keratinocytes through a proteasome-dependent mechanism. Reducing the expression of TTP functionally promoted tumor growth of H-rasV12 expressing HKCs, while stabilizing TTP expression counteracted the tumor-promoting effects of calcineurin inhibition. Collectively these results suggest that calcineurin signaling, acting through TTP protein level stabilization, suppresses keratinocyte tumors by downregulating skin inflammation.

Swiss (German) Version of the Actinic Keratosis Quality of Life questionnaire.

BACKGROUND: Actinic keratosis (AK) is a sun-induced skin lesion that may progress to invasive squamous cell carcinoma of the skin. Recently, the Actinic Keratosis Quality of Life questionnaire (AKQoL) was designed for patients with AK in Denmark as a specific quality of life instrument for AK patients. OBJECTIVE: The objective of this study was to adapt the AKQoL for the German language region of Switzerland and to evaluate its psychometric properties (validity, reliability). METHODS: Translation and cultural adaptation of the questionnaire were assessed by using the technique of cognitive interviewing. During the translation process, 34 patients with AK from the Department of Dermatology, University Hospital Zurich, were interviewed in 3 sessions of cognitive interviewing. The translated questionnaire was then distributed together with the Dermatology Life Quality Index (DLQI) to a second group of 113 patients for validation and reliability testing. Within this group, we measured the internal consistency by the Cronbach coefficient α and Spearman correlation coefficient between the AKQoL and the DLQI. RESULTS: The problems encountered during the translation process led to changes in 5 categories as described by Epstein: stylistic changes, change in breadth, change in actual meaning, change in frequency and time frame, change in intensity. We found a Cronbach α of 0.82, an acceptable internal consistency. The Spearman correlation coefficient between total scores of AKQoL and DLQI was 0.57. CONCLUSION: We culturally adapted and validated a Swiss (German) version of the AKQoL questionnaire applicable for the population of a university center in Switzerland to measure and monitor the quality of life in patients with AK.

TLR4 as a negative regulator of keratinocyte proliferation.

TLR4 is an innate immune receptor with expression in human skin, keratinocytes as well as squamous cell carcinoma (SCC) of the skin. In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with the differentiation of cultured keratinocytes in a passage-dependent manner or under calcium-rich conditions. Moreover, the down-regulation of TLR4 by specific knockdown increased the proliferation of HaCaT keratinocytes in vitro. In addition, subcutaneously injected HaCaT keratinocytes with shTLR4 formed growing tumors in nude mice. In contrast, we observed lower proliferation and increased migration in vitro of the SCC13 cell line stably overexpressing TLR4 in comparison to SCC13 TLR4 negative cells. In vivo, SCC13 TLR4-overexpressing tumors showed delayed growth in comparison to TLR4 negative tumors. The overexpression of TLR4 in SCC13 tumor cells was followed by phosphorylation of ERK1/2 and JNK and increased expression of ATF3. In gene expression arrays, the overexpression of TLR4 in tumor cells correlated with gene expression of ATF-3, IL-6, CDH13, CXCL-1 and TFPI. In summary, TLR4 negatively regulates the proliferation of keratinocytes and its overexpression reduces tumor growth of SCC cells.

Considerations on long-term immuno-intervention in the treatment of multiple sclerosis: an expert opinion.

INTRODUCTION: As management of multiple sclerosis (MS) requires life-long treatment with disease-modifying agents, any risks associated with long-term use should be considered when evaluating therapeutic options. AREAS COVERED: Immune cells of the innate and adaptive immune systems play various roles in the pathogenesis of MS. MS therapies affect the immune system, each with a unique mode of action, and consequently possess different long-term safety profiles. Rare, but serious safety concerns, including an increased risk of infection and cancer, have been associated with immunosuppressant use. The risks associated with newer immunosuppressive agents, which target specific elements of MS disease pathophysiology, are not yet fully established as the duration of clinical trials is relatively short and post-marketing experience is limited. Non-immunosuppressants used to treat MS have well-defined safety profiles established over a large number of patient-years demonstrating them to be well-tolerated long-term treatment options. When considering the long-term use of disease-modifying agents for treating MS, classification as immunosuppressants or non-immunosuppressants can be useful when evaluating potential risks associated with chronic use. EXPERT OPINION: A successful therapeutic strategy for any serious, chronic disease such as MS should weigh effectiveness versus long-term safety of available treatments.

Ingenol Mebutate 150 mg as Physician-Directed Treatment of Bowen's Disease Under Occlusion.

Ingenol mebutate (IM) is a topical pharmacotherapy approved in Switzerland since 2012 for treating non-hypertrophic, non-hyperkeratotic actinic keratosis. We report a case with off-label use of IM where Bowen's disease has been successfully treated with physician-directed IM 0.015% gel under occlusion over the chest area.

Bowenoid Actinic Keratosis and Bowen's Disease Treated Successfully with Ingenol Mebutate.

Ingenol mebutate (IM) is a topical pharmacotherapy approved in Switzerland since 2012 for treating non-hypertrophic, non-hyperkeratotic actinic keratosis (AK). We report 2 cases with off-label use of IM. The first case of bowenoid AK was treated with 150 µg IM for 3 consecutive days with an almost complete clinical remission of the lesion. The second case of Bowen's disease was treated with 500 µg IM for 2 consecutive days leading to complete clinical remission.

Ingenol Mebutate Signals via PKC/MEK/ERK in Keratinocytes and Induces Interleukin Decoy Receptors IL1R2 and IL13RA2.

Squamous cell carcinoma (SCC) is the second most common human skin cancer and the second leading cause of skin cancer-related death. Recently, a new compound, ingenol mebutate, was approved for treatment of actinic keratosis, a precursor of SCC. As the mechanism of action is poorly understood, we have further investigated the mechanism of ingenol mebutate-induced cell death. We elucidate direct effects of ingenol mebutate on primary keratinocytes, patient-derived SCC cells, and a SCC cell line. Transcriptional profiling followed by pathway analysis was performed on ingenol mebutate-treated primary keratinocytes and patient-derived SCC cells to find key mediators and identify the mechanism of action. Activation of the resulting pathways was confirmed in cells and human skin explants and supported by a phosphorylation screen of treated primary cells. The necessity of these pathways was demonstrated by inhibition of certain pathway components. Ingenol mebutate inhibited viability and proliferation of all keratinocyte-derived cells in a biphasic manner. Transcriptional profiling identified the involvement of PKC/MEK/ERK signaling in the mechanism of action and inhibition of this signaling pathway rescued ingenol mebutate-induced cell death after treatment with 100 nmol/L ingenol mebutate, the optimal concentration for the first peak of response. We found the interleukin decoy receptors IL1R2 and IL13RA2 induced by ingenol mebutate in a PKC/MEK/ERK-dependent manner. Furthermore, siRNA knockdown of IL1R2 and IL13RA2 partially rescued ingenol mebutate-treated cells. In conclusion, we have shown that ingenol mebutate-induced cell death is mediated through the PKCδ/MEK/ERK pathway, and we have functionally linked the downstream induction of IL1R2 and IL13RA2 expression to the reduced viability of ingenol mebutate-treated cells.

S100A8/A9 stimulates keratinocyte proliferation in the development of squamous cell carcinoma of the skin via the receptor for advanced glycation-end products.

Squamous cell carcinoma (SCC) is the most common neoplasm in organ transplant recipients (OTR) on long-term immunosuppression and occurs 60- to 100-fold more frequently than in the general population. Here, we present the receptor for advanced glycation end products (RAGE) and S100A8/A9 as important factors driving normal and tumor keratinocyte proliferation. RAGE and S100A8/A9 were transcriptionally upregulated in SCC compared to normal epidermis, as well as in OTR compared to immunocompetent patients (IC) with SCC. The proliferation of normal and SCC keratinocytes was induced by exposure to exogenous S100A8/A9 which in turn was abolished by blocking of RAGE. The migratory activities of normal and SCC keratinocytes were also increased upon exposure to S100A8/A9. We demonstrated that exogenous S100A8/A9 induces phosphorylation of p38 and SAPK/JNK followed by activation of ERK1/2. We hypothesize that RAGE and S100A8/A9 contribute to the development of human SCC by modulating keratinocyte growth and migration. These processes do not seem to be impaired by profound drug-mediated immunosuppression in OTR.

Keratinocyte cancer and its precursors in organ transplant patients.

Organ transplant recipients (OTRs) have a 65- to 250-fold increased risk of the development of cutaneous squamous cell carcinoma in the wake of immunosuppression. The combination of ultraviolet light and properties of immunosuppressive drugs potentiate skin cancer formation. Due to decreased peritumoral inflammation, the thickness and invasion of epithelial skin lesions are often underestimated clinically. Rapid tumor progression and aggressive tumor behaviors occur frequently in the OTR population. Tenderness and pain in a skin lesion may indicate its potential invasion beyond the basal membrane and the need for surgical removal. All patients should receive extensive education on ultraviolet avoidance and protection. In particular, a preventive and aggressive treatment of actinic keratosis in areas of field cancerization is recommended to cut down on the high morbidity and avoid the mortality associated with actinic keratosis and invasive squamous cell carcinoma in OTRs.

Borrelial pseudolymphoma of the nose.

A 52-year-old Colombian woman, a patient with psoriasis, undergoing phototherapy with (ultraviolet B narrowband) UVBnb, presented with a symptomless solitary diffuse erythaematous plaque on her nose for 3 months. Initially, she was treated with pimecrolimus 1% cream for 8 weeks, which was then combined with metronidazole cream for 4 weeks, with the initial diagnosis of UV-triggered rosacea, without improvement. A punch biopsy was performed and the histology showed a pseudolymphomatous reaction. The diagnosis of nasal pseudolymphoma of borreliosis was confirmed with PCR. The lesion completely resolved following oral doxycycline therapy.

Cetuximab in metastatic squamous cell cancer of the skin: a Swiss case series.

BACKGROUND: There is current evidence that non-melanoma skin cancers can be successfully treated with cetuximab. OBJECTIVE: To evaluate the use and efficacy of cetuximab (with or without radiotherapy) in a series of previously treated patients with metastatic squamous cell cancer of the skin (SCCS) in Switzerland. METHODS: We performed a retrospective analysis of six patients from four centers. Endpoints were disease control rates (DCRs) at 4-8 weeks, 12-14 weeks and 20-36 weeks of treatment. Treatment-related toxicity was evaluated additionally. RESULTS: A median of 14 cycles of cetuximab were applied. DCR was 67% at 4-8 weeks, 50% at 12-14 weeks and 33% at 20-36 weeks. In 4-8 weeks responders, mean relapse-free time was 12 ± 6.2 months and mean overall survival was 25 ± 16.2 months. Grade I-III acne-like rash developed around week 3 of treatment in 83%. CONCLUSIONS: Cetuximab treatment in patients with metastatic SCCS achieved an overall DCR of 67% at 4-8 weeks of treatment. This study underlines the current evidence that SCCS can be successfully treated with cetuximab.

Multifactorial ERß and NOTCH1 control of squamous differentiation and cancer.

Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor ß (ERß) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERß controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERß, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERß-dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERß expression or treatment with ERß agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer.