Dermatology issues in solid organ transplant recipients
Authors: DJ Eedy
Journal: British Journal of Dermatology (2006)

It was over 50 years ago, on 23 December 1954, when the first renal transplantation operation between identical twins was undertaken in Boston.1 Although the operation was a success and some renal function was restored in the recipient, the kidney had to be removed at a later stage because hypertension developed. It was not until the so-called azathioprine era, starting in the 1960s, that an alternative to dialysis became practical and led to a surge in renal transplantation and to the early efforts in liver, heart and pancreas transplantation.1 In the early 1980s, ciclosporin, a calcineurin inhibitor, was introduced, and led to a marked reduction in the loss of kidneys from rejection, as well as a dramatic improvement in the outcome of liver and heart transplantation. This issue of the BJD carries five papers, which illustrate the problems that arise as a result of the improvements in management of patients who have received the transplant of a solid organ, a topic which has been studied most closely in renal transplant recipients (RTRs). Successful transplantation has resulted in patients continuing on immunosuppression for decades. This dramatically improved patient and graft survival after transplantation has led to the well documented increase in nonmelanoma skin cancer (NMSC) – a particular problem in those countries mainly populated by fair-skinned people who often have a high occupational and recreational sun exposure. Transplantation in older age group patients and the longer duration of immunosuppression has led to a well recognized increased need for surveillance and treatment of NMSC in these patients.2 Moloney et al.2 showed a very high rate of NMSC in RTRs of under 50 years of age with an incidence rate over 200 times that expected in the population. For those RTRs over 50 years of age the rate of NMSC rose even more, perhaps representing the release of damaged clones of cells which had previously been held under immune control.2 The authors point to the need for regular surveillance of RTRs, patient education, changing to newer immunosuppressive therapies and the reduction or even withdrawal of immunosuppression when tumorigenesis emerges as a clinical problem. Their study showed a 6·6-fold increase in melanoma and 97-fold increase in Kaposi sarcoma in RTRs, though because of the study size the numbers were too small for precise statistical analysis.2 At the recent Skin Care in Organ Recipients meeting in London held on 10 November 2005 (SCOR UK) primary chemoprevention of NMSC threw up the interesting observation that polyphenols in black and, particularly, in green tea are powerful antioxidants. Professor Eggert Stockfleth pointed to the possibility that polyphenol E ointment could be used as a topical chemopreventative agent, particularly in actinically damaged skin. A topical preparation will be necessary, as a therapeutic effect from drinking green tea alone would require the drinking of some 240 cups of green tea per day! He reintroduced the concept of progressive development of keratinocyte intraepithelial neoplasia (KIN). He suggested that we should consider keratinocyte atypia graded as mild (KIN I), moderate (KIN II) or severe (KIN III).3 KIN I lesions are characterized by flat, pink macules; histologically the nuclei of these basal and suprabasal cells are hyperchromatic and contain small but prominent nucleoli.3 There is no overlying hyperkeratosis or parakeratosis. In the next stage of progression KIN II has plaques, which are rough and hyperkeratotic; the basal and suprabasal layers show an increase in the number of mitotic figures, and there may be eosinophilia, basophilia, dyskeratosis or clear cells. The lesions of KIN III are currently referred to as squamous cell carcinoma in situ or Bowen's disease. At the SCOR UK meeting Stockfleth took us through the common treatment of premalignant skin conditions to include surgical excision, dermabrasion, curettage, cryotherapy, chemical peels, laser treatment, photodynamic therapy, imiquimod, 5-fluorouracil, retinoids and diclofenac in hyaluronic acid gel. In forthcoming issue of the journal a paper from Professor Stockfleth's department (Ulrich et al.4) will provide evidence in a small open label controlled pilot study that imiquimod 5% cream may be useful in the treatment of local precancerous lesions in patients who have an organ transplant.4 In a further paper by de Graaf et al.5 the authors seem to indicate that the use of curettage and electrodessication can be a safe therapy for appropriately selected low risk squamous cell carcinomas although their recurrence rate of 6% is higher than in a previous series in immunocompetent patients. They do emphasize that curettage and electrodessication should only be performed by someone who has experience with this procedure. In the present issue of the journal the group from Oxford present data on melanoma in RTRs and found an approximately 10-fold increase in incidence in melanoma in the Oxford renal transplant population.6 This is rather higher than previous reports, which tended to be in the range of a two- to fivefold increase in incidence in RTRs. Although a 10-fold increase is the highest rate reported in the literature, the patients appear to have a good outcome and this may be because RTRs attend dedicated dermatology clinics; a plan that possibly contributed to early diagnosis and better outcomes. The issue of melanoma developing as a risk after transplanting kidneys from donors who have previously had melanoma has been well reported to date7, 8 and underlines the need to exclude as organ donors patients who had suffered from invasive cancers. The precise situation regarding melanoma developing after transplantation (as a result of immunosuppression) requires further study because no single study to date has had sufficient power to demonstrate the increased risk, although the data points to a moderately increased risk after transplantation.9 In a review of the newer drugs used in transplantation, Mahe et al. pointed out the differences between older drugs such as the calcineurin inhibitors (ciclosporin, tacrolimus) and the newer mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus). Not only do tacrolimus, ciclosporin and sirolimus have different mechanisms of action, the mTOR inhibitors may inhibit endothelial cell proliferation, have antitumour properties and are possibly less nephrotoxic. They can be used either in combination with ciclosporin (reducing its dose), allowing the withdrawal of ciclosporin by conversion to sirolimus or as a base therapy, thus avoiding ciclosporin from the beginning of transplantation. Sirolimus can, in addition, be combined with mycophenolate mofetil and steroids. Dermatological complications of sirolimus are frequently of pilosebaceous origin and include acneiform eruptions, scalp folliculitis, hidradenitis suppurativa, and problems of oedema including chronic oedema and angio-oedema.10 Mucous membrane side-effects are common with aphthous ulceration and epistaxis occurring in up to 60% of patients, and also includes chronic gingivitis and fissuring of the lips. Nail disorders include chronic onychopathy and periungual infections. Among the commonest side-effects of sirolimus-based immunosuppressive therapy are pneumonitis, hyperlipidaemia, anaemia and proteinuria. Given the frequent need to change or reduce immunosuppression in transplant-associated skin cancer, the expert consensus panel published in this issue of the journal11 provides good guidelines for the reduction of immunosuppression in various possible cancer situations in organ transplant patients. The tables point out the potential risk to the allograft while giving speculative models for a wide range of skin cancers. The group did not appear to address the issue of changing immunosuppression to other agents such as sirolimus but this has been addressed elsewhere.12 Dr Meg Price (Brighton, U.K.) pointed out that the British Association of Dermatologists (BAD) have now prepared two information sheets (available from the BAD website) regarding advice on skin cancer for patients awaiting organ transplant and for those with an organ transplant. These will be helpful in the clinic. At SCOR UK the issue of inflammatory skin disease in organ recipients was addressed. Professor Fennella Wojnarowska looked at 200 of the Oxford Group RTRs and found that of inflammatory skin disorders 11% had acne, 4% rosacea, 2% perioral dermatitis and 2% acne keloidalis nuchae. In addition she reported that seborrhoeic eczema was more difficult to bring under control than in the average patient. Other skin conditions included photo telangiectasia, pigmentary disorders, skin fragility, xerosis, purpura and problems related to treatment side-effects including sebaceous gland hyperplasia, hypertrichosis and gingival hypertrophy. Much more work appears to be required in this area and it has to date been a largely neglected area of dermatology. Finally, as editor of the BJD I do hope you find the cluster of papers in this issue constructive, and, for those of you who managed to get to the second meeting of SCOR UK I hope you enjoyed it as much as I did; for those of you who did not, I hope my brief synopsis will wet your appetite.