C. Ulrich

Skin Cancer in Organ Transplant Recipients—Where Do We Stand Today?

Skin cancers are the most frequent malignancies in organ transplant recipients (OTR), with 95% being nonmelanoma skin cancers (NMSC), especially squamous (SCC) and basal cell carcinomas. Most OTR with a first SCC subsequently develop multiple NMSC within 5 years, highlighting the concept of ‘field cancerization’, and are also at high risk for noncutaneous cancers. In order to reduce the tumor burden in these patients, their management requires an interdisciplinary approach including revision of immunosuppression, new dermatological treatments and adequate education about photoprotection in specialized dermatology clinics for OTR. Whereas surgery remains the gold‐standard therapy for NMSC, noninvasive methods have shown promising results to treat superficial keratoses and subclinical lesions on large body areas. Although the threshold of skin cancer necessitating revision of immunosuppression is debated, this measure should be envisaged at the occurrence of the first SCC, or in case of multiple non‐SCC NMSC. While the role of immunosuppressants in the occurrence of NMSC is widely recognized, the best immunosuppressive strategies remain to be defined. Presently, randomized prospective studies assess the burden of new skin tumors, as well as graft and patient survival, in patients with one or several NMSC after the introduction of mTOR (mammalian target of rapamycin) inhibitors.

Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study

Background  Skin cancers represent a major challenge within the ever growing group of long time surviving organ transplant recipients (OTR) world wide. Especially UV‐induced non‐melanoma skin cancers (NMSC) like invasive squamous cell carcinomas (SCC) and actinic keratoses (AK), and basal cell carcinoma (BCC), outnumber every other form of cancer in organ transplant recipients. Despite encouraging reports of protective effects of broad‐spectrum sunscreens in immunocompetent patients, evidence for the prevention of NMSC in immunocompromised patients is still missing.

Actinic keratosis is an early in situ squamous cell carcinoma: A proposal for reclassification

Summary The term actinic keratosis (AK) describes a sun‐induced, clinical erythematous lesion covered with scale, but does not provide an understanding of the biology or histopathology of the lesion. Cousequeutly, several classification systems for AK have been suggested, but as yet no cousensus has been reached. These systems strive to correlate the pathological and clinical features to better provide physcians with the most accurate information to enable correct decisions to be made regarding treatments, Prognosis and metastatic potential. AK is a clinical description that has a histological diagnosis consistent with squamous cell carcinoma (SCC) in situ. We recommend an AK classification system that describes these lesions as squamous cell carcinomas (SCCs), using the terminology ‘early in situ SCC Type AK I’, ‘early in situ SCC type AK II’ and ‘in situ SCC Type AK III’, there by giving clinicians better guidance for diagnosis and specific treatment recommendations.

Epidemiology of nonmelanoma skin cancer (NMSC) in Europe: Accurate and comparable data are needed for effective public health monitoring and interventions

Summary Nonmelanoma skin cancer (NMSC) is the most common malignancy occurring in white populations. It is currently becoming an important challenge in terms of public health management as the increasing incidence rates will probably have a tremendous impact on healthcare costs. Possible factors driving this rise in NMSC numbers are increases in both acute and prolonged UV exposure together with increasing numbers of older people in the population. A better understanding of NMSC epidemiology in Europe is essential if an evidence‐based European‐wide public health policy is to be developed. It is obvious this can only be achieved by recording and analysing comparative epidemiological data. Finally, by improving the skin examination training for physicians, developing guidelines and exchanging best practices, a high level of healthcare could be provided for NMSC.

Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients.

Objective  In this study the safety and efficacy of imiquimod 5% cream for the treatments of actinic keratoses in kidney, heart and liver transplant recipients is evaluated.

Induction of apoptosis by Toll-like receptor-7 agonist in tissue cultures.

Toll‐like receptor (TLR)‐7 agonists represent a new group of immune response modifiers, which include imiquimod and resiquimod (R‐848). Topically applied imiquimod is used for the treatment of both external and perianal genital warts, and benign and malignant epithelial lesions. Based on the induction of interferons and other cytokines in vitro and in vivo, regression of epithelial lesions probably depends on induction of both innate and cellular immune responses. As clinical remission is not always associated with inflammation, other mechanisms may also be involved. Using two different assays for detection of apoptosis (TUNEL test and gel analysis of DNA fragmentation), we observed induction of apoptosis by imiquimod in human epithelial cell lines (HeLa S3) and keratinocytes (HaCaT, A431 cells), as well as in mouse fibroblasts (McCoy cells). These findings suggest that the mode of action of imiquimod to eliminate virus‐infected, dysplastic or neoplastic epithelial cells may also include the induction of apoptotic processes.

The role of apoptosis in therapy and prophylaxis of epithelial tumours by nonsteroidal anti‐inflammatory drugs (NSAIDs)

Summary In addition to having anti‐inflammatory activities, nonsteroidal anti‐inflammatory drugs (NSAIDs) also inhibit neoplastic cell proliferation by inducing apoptosis. Diclofenac is the anti‐neoplastic compound in diclofenac 3% gel (SolarazeTM) used for topical treatment of actinic keratosis (AK). Main target of NSAIDs seems to be the inhibition of cyclo‐oxygenase‐2 (COX‐2), which is overexpressed in several epithelial tumours and catalyses the synthesis of prostaglandins. The precise mechanism of action of diclofenac in cutaneous cells is still unclear, but induction of apoptosis is a key effect of anti‐neoplastic drugs, including NSAIDs.

Apoptosis pathways as promising targets for skin cancer therapy

Summary Apoptosis pathways provide efficient safeguard mechanisms against cancer that are mediated via cell‐intrinsic responses and immune‐mediated extrinsic signals. Intrinsic pro‐apoptotic pathways are largely controlled by p53 and Bcl‐2 proteins, whereas the extrinsic induction of apoptosis is initiated by death ligands, such as tumour necrosis factor‐alpha (TNF‐α), CD95L/FasL and TNF‐related apoptosis‐inducing ligand (TRAIL), or by granzyme B. Initiation of these pathways results in the induction of a caspase cascade leading to cell death.

Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses

Increasing incidence rates of cutaneous malignancies, paralleling rising survival times of grafts and patients in organ transplant recipients, represents an escalating challenge for dermatologists worldwide. Especially, invasive squamous cell carcinomas (SCC) in immuno-compromised patients are characterized by significantly increased morbidity and mortality and characteristically outnumber basal cell carcinoma in this population. Effective management of actinic keratoses (AK) could help to prevent the further development of invasive SCC. Diclofenac in hyaluronic acid has previously shown to be an effective and well tolerated option for the treatment of AK in immuno-competent patients. However, its safety and efficacy in organ-transplant patients has not been evaluated in a controlled study so far. 32 organ transplant patients (kidney (+/- pancreas), liver, heart) screened at our specialized transplant dermatology outpatient clinic were found eligible and were randomized to either active treatment (24) or vehicle (8). Patients who had stable status of the transplanted graft in the 12 months prior to entering the study and >/= 3 AK lesions in a contiguous 50 cm2 area on the face, forehead, hands or balding scalp were eligible for inclusion in the study. Treatment of AK with 3% diclofenac in 2.5% hyaluronic acid or placebo twice daily was conducted over a total of 16 weeks, followed by a final evaluation 4 weeks after last application of the study drug. Biopsies were taken from the treated areas at the final visit to verify clinical clearance. Patients were assessed for safety variables that included adverse events, local skin reactions, laboratory results, dosage of immunosuppressive medication and indication of graft rejection. A 24 months follow up was conducted after the end of treatment. 87% (n = 28/32) of the patients completed the 16 week treatment phase and presented for final evaluation 4 weeks after end of treatment. In the diclofenac 3% gel treatment group, a complete clearance of AK lesions was achieved in 41% (9/22) compared to 0% (0/6) in the vehicle group. Side effects in most of the patients included a mild erythema and a mild to moderate swelling of the areas treated. No graft rejections or trends for a deterioration of graft function were detected. No meaningful trends were observed in laboratory results. In 55% of the previously cleared patients, new AK developed in the study area after an average of 9.3 months. None of these patients developed invasive SCC in the study area within 24 months of follow-up. This study demonstrated a greater lesion clearance rate of AKs in OTRs treated with diclofenac 3% gel than with vehicle. Despite recurrent AK in 55% of the previously cleared patients, the 24 month results showed no invasive SCC in this group. This study suggests that diclofenac 3% gel is not only an efficient and well tolerated treatment for multiple AKs in OTRs but also may prevent invasive SCC in these high-risk patients.

Successful treatment of multiple actinic keratoses in organ transplant patients with topical 5% imiquimod: a report of six cases.

Background  Nonmelanoma skin cancer represents a significant cause of morbidity in organ transplant recipients (OTRs). Cutaneous malignancies, mainly invasive squamous cell carcinoma and its precursor actinic keratosis (AK), appear approximately 5–10 years after organ transplantation. Impaired wound healing and high recurrence rates in immunocompromised patients treated with destructive therapies such as cryosurgery or topical 5‐fluorouracil represent frequently known complications.