Conal M. Perrett

Treatment of post-transplant premalignant skin disease: a randomized intrapatient comparative study of 5-fluorouracil cream and topical photodynamic therapy.

Background  Organ transplant recipients (OTR) are at high risk of developing nonmelanoma skin cancer and premalignant epidermal dysplasia (carcinoma in situ/ Bowens disease and actinic keratoses). Epidermal dysplasia is often widespread and there are few comparative studies of available treatments.

Azathioprine treatment photosensitizes human skin to ultraviolet A radiation

Background  Azathioprine is used to treat a variety of conditions and to prevent graft rejection in organ transplant recipients (OTRs).

Reactive oxygen-mediated damage to a human DNA replication and repair protein

Ultraviolet A (UVA) makes up more than 90% of incident terrestrial ultraviolet radiation. Unlike shorter wavelength UVB, which damages DNA directly, UVA is absorbed poorly by DNA and is therefore considered to be less hazardous. Organ transplant patients treated with the immunosuppressant azathioprine frequently develop skin cancer. Their DNA contains 6‐thioguanine—a base analogue that generates DNA‐damaging singlet oxygen (1O2) when exposed to UVA. Here, we show that this 1O2 damages proliferating cell nuclear antigen (PCNA), the homotrimeric DNA polymerase sliding clamp. It causes covalent oxidative crosslinking between the PCNA subunits through a histidine residue in the intersubunit domain. Crosslinking also occurs after treatment with higher—although still moderate—doses of UVA alone or with chemical oxidants. Chronic accumulation of oxidized proteins is linked to neurodegenerative disorders and ageing. Our findings identify oxidative damage to an important DNA replication and repair protein as a previously unrecognized hazard of acute oxidative stress.

Etanercept-induced systemic lupus erythematosus

Tumour necrosis factor (TNF) is a pro‐inflammatory cytokine with a role in the pathogenesis of a number of conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohns disease. Etanercept (Enbrel®; Immunex Corp., Seattle, WA, USA) is a recombinant soluble fusion protein of TNF‐α type II receptor and IgG which acts by blocking the action of TNF‐α. It is licensed for use in rheumatoid arthritis and juvenile chronic arthritis. A number of studies report the development of antinuclear and anti‐double‐stranded DNA antibodies in patients treated with TNF antagonists for rheumatoid arthritis. There are few reports of the development of clinical features of discoid, subacute or systemic lupus erythematosus. We present one of the first reported cases of etenercept‐induced systemic lupus erythematosus and review the literature of lupus and TNF antagonists.

Imiquimod cream 5% for recalcitrant cutaneous warts in immunosuppressed individuals.

Background  Viral warts may cause significant morbidity in individuals unable to mount an adequate T‐helper 1 cell‐mediated immune response to human papillomavirus. Imiquimod is a potent inducer of antiviral cytokine activity which has shown significant efficacy in the treatment of genital warts. Similar efficacy in cutaneous warts is not yet established.

PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients.

The immunosuppressant azathioprine is used to prevent graft rejection after organ transplantation. To investigate whether azathioprine-associated mutagenesis contributes to the high incidence of skin tumours in organ transplant recipients (OTRs), we analysed PTCH gene mutations in 60 basal cell carcinomas (BCC); 39 from OTRs receiving azathioprine and 21 from individuals never exposed to azathioprine. PTCH was mutated in 55% of all tumours, independent of azathioprine treatment. In both the azathioprine and non-azathioprine groups, transitions at dipyrimidine sequences, considered to indicate mutation by ultraviolet-B radiation, occurred frequently in tumours from chronically sun-exposed skin. In BCC from non-sun-exposed skin of azathioprine-treated patients, there was an over-representation of unusual G:C to A:T transitions at non-dipyrimidine sites. These were exclusive to the azathioprine-exposed group and all in the same TGTC sequence context at different positions within PTCH. Meta-analysis of 247 BCCs from published studies indicated that these mutations are rare in sporadic BCC and had never previously been reported in this specific sequence context. This study of post-transplant BCC provides the first indication that azathioprine exposure may be associated with PTCH mutations, particularly in tumours from non-sun-exposed skin.

Cyclosporin in childhood psoriasis

background: Cyclosporin is known to be highly effective in the treatment of psoriasis in adults. It has also proved effective and well tolerated in the treatment of severe childhood atopic dermatitis. Psoriasis in childhood is relatively unusual but by no means rare and on occasions the disease can be very difficult to control in this age group. The use of cyclosporin for psoriasis in childhood has received scarcely any attention and in the few cases that have been reported the results have been inconsistent. Three children aged from 7 to 11 years with severe psoriasis resistant to topical agents were treated with cyclosporin. The highest dose required was 3.5 mg/kg per day. The duration of treatment ranged from 6 weeks to 4 months. Cyclosporin was effective and generally well tolerated. Treatment was interrupted in one case due to nausea and diarrhoea. None of the patients developed hypertension or renal impairment. The potential role of cyclosporin in severe childhood psoriasis is discussed.

Tea tree oil dermatitis associated with linear IgA disease.

Tea tree oil dermatitis is an increasingly common finding, reflecting the strong demand for natural remedies and aromatic substances. Linear immunoglobulin A (IgA) disease is a rare acquired subepidermal blistering disorder, characterized by basement membrane zone IgA deposition. We describe a patient in whom linear IgA disease appears to have been precipitated by a contact reaction to tea tree oil.

Vulval intraepithelial neoplasia and periungual Bowen's disease concordant for mucosal (HPV-34) and epidermodysplasia verruciformis (HPV-21) human papillomavirus types

Human papillomavirus (HPV) infection is associated with genital malignancy and specific cutaneous malignancies. We report a case of an HPV‐associated concurrent vulval intraepithelial neoplasia and periungual Bowens disease in a young immunocompetent Afro‐Caribbean woman with no known risk factors for either disease. HPV genotyping studies detected multiple α and β papillomaviruses with concordance for HPV‐34 [a high‐risk (HR) mucosal type], and HPV‐21 [an epidermodyslasia verruciformis (EV) type] in both vulval and finger tissue. Although the HR‐mucosal viruses detected are likely to have a pathogenic role in vulval intraepithelial neoplasia, this is the first report of concordance for EV HPV types in both genital and nongenital skin premalignancies. This case, in the context of accumulating epidemiological and experimental data in cutaneous SCC, raises the question of whether EV HPV may contribute to vulval malignancy, and further study is merited.

Atypical fibroxanthoma in a renal transplant recipient.

Sir: It is well established that organ transplant recipients receiving long-term immunosuppressive therapy are at an increased risk of developing cutaneous malignancies, of which squamous cell carcinoma (SCC) is the commonest. Atypical fibroxanthoma (AFX) is a rare cutaneous mesenchymal tumour which has been reported in organ transplant recipients on only three previous occasions. We report a further case in a renal transplant recipient which illustrates the potential diagnostic challenge posed by such cases. A 44-year-old caucasian man, Fitzpatrick skin type 2, underwent renal transplantation in 1990 for end-stage renal failure secondary to membranous glomerulonephritis. Post-transplantation he was commenced on prednisolone 10 mg daily, azathioprine 100 mg daily and cyclosporin 250 mg daily and was kept under regular surveillance in a dedicated organ transplant skin clinic. Within 2 years of transplantation he had developed multiple viral warts and by 2003 he had developed a total of 11 SCCs, two basal cell carcinomas, and 19 SCCs in situ, all on sun-exposed sites. In April 2003 a tender, red, ulcerated nodule measuring 15 mm in diameter developed on the left side of his neck. It was diagnosed clinically as an SCC and was excised. Histological examination (Figure 1) revealed a well-circumscribed, non-encapsulated, highly cellular tumour centred on the dermis. It was composed of pleomorphic, spindle-shaped and epithelioid cells arranged in sheets and fascicles, with a high mitotic rate (Figure 1). Some scattered cells were polyhedral and vacuolated with lipid-containing cytoplasm. These features were consistent with an undifferentiated malignant spindle cell skin tumour. To examine histogenesis further, immunohistochemistry with a panel of antibodies was performed; labelling of tumour cells was positive for vimentin and strongly positive for CD99 (Figure 2), and negative for cytokeratins, S100 protein, CD15, CD34, CD68, MNF 116, smooth muscle actin, HMB 45 antigen, desmin, PGP 9.5, a-antitrypsin, a1-antichymotrypsin, KP1, and factor XI-IIa. In addition, electron microscopy showed abundant endoplasmic reticulum, large cell nuclei, prominent nucleoli and irregular outline; several cells Figure 1. Upper dermal tumour composed of pleomorphic spindle-shaped cells and epithelioid cells arranged in sheets and fascicles.