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• W2018889597 abstract "A 69-year-old man, with a history of end-stage renal disease due to polyarteritis nodosa, followed by invasive pulmonary aspergillosis secondary to cyclophosphamide and corticosteroids, received a renal transplant 2 years ago under prophylactic treatment with voriconazole. Because of the severity of the aspergillosis, it was decided to continue voriconazole for a prolonged period. Eighteen months after transplantation, the patient developed a severe facial phototoxic reaction. A few months later, he developed multiple actinic keratoses and a large, rapidly expanding, poorly differentiated squamous cell carcinoma (SCC) with perineural invasion and metastatic lymph nodes, necessitating radical surgery and radiotherapy. Voriconazole therapy has been suggested to be involved in the development of multi-focal invasive SCC when complicated by a phototoxic reaction. Therefore, an alternative antifungal prophylaxis regimen (for instance with posaconazole) should be considered when evaluating patients for solid organ transplantation who are at high risk for the development of cutaneous malignancies. A 69-year-old man, with a history of end-stage renal disease due to polyarteritis nodosa, followed by invasive pulmonary aspergillosis secondary to cyclophosphamide and corticosteroids, received a renal transplant 2 years ago under prophylactic treatment with voriconazole. Because of the severity of the aspergillosis, it was decided to continue voriconazole for a prolonged period. Eighteen months after transplantation, the patient developed a severe facial phototoxic reaction. A few months later, he developed multiple actinic keratoses and a large, rapidly expanding, poorly differentiated squamous cell carcinoma (SCC) with perineural invasion and metastatic lymph nodes, necessitating radical surgery and radiotherapy. Voriconazole therapy has been suggested to be involved in the development of multi-focal invasive SCC when complicated by a phototoxic reaction. Therefore, an alternative antifungal prophylaxis regimen (for instance with posaconazole) should be considered when evaluating patients for solid organ transplantation who are at high risk for the development of cutaneous malignancies. A 69-year-old Caucasian male (with a history of long periods of intensive sun exposition, because he worked for decades in the Middle East) developed rapidly progressive glomerulonephritis due to polyarteritis nodosa in January 2003, for which he received intravenous pulses of cyc-lophosphamide (CYC, Endoxan®, Baxter, Halle, Germany) and corticosteroids (CS, methylprednisolone, Medrol®, David Bull Laboratories Pvt Ltd, Mulgrave, Australia). Despite this treatment, he evolved to end-stage renal disease for which chronic intermittent hemodialysis was started. However, the immunosuppressive treatment was complicated with an invasive pulmonary aspergillosis, successfully treated with intravenous amphotericin B lipid complex (Abelcet®, Zeneus, Eindhoven, The Netherlands) for a period of 6 weeks. He was evaluated for renal transplantation one year after complete recovery (apart from end-stage renal disease). He received a deceased donor kidney in June 2005, using CS, mycophenolate mofetil (MMF, Cellcept®, Hoffmann-LaRoche, Basel, Switzerland), tacrolimus (TAC, Prograft®, Fujisawa GmbH, Munich, Germany) and basiliximab (Simulect®, Novartis, Basel, Switzerland) as induction immunosuppressive therapy. Maintenance immunosuppressive therapy consisted of CS (methylprednisolone 2 mg/day) and TAC 2 mg/day (corresponding with a tacrolimus predose level of 5 to 7 μg/L), resulting in adequate long-term graft function (serum creatinine between 1.6 and 1.7 mg/dL, corresponding to a creatinine clearance of 35 to 40 mL/min). Because of his history of invasive aspergillosis, it was decided to associate prophylactic treatment with oral voriconazole (Vfend®, Pfizer Limited, Kent, UK) for a period of 1 to 2 years after renal transplantation. In a follow-up period of 2 years posttransplantation, no recurrence of invasive aspergillosis was noted clinically or radiographically and regular galactomannan antigen assays remained negative. Fifteen months after renal transplantation, he developed an erythematous phototoxicity reaction affecting all sun-exposed skin; however, it was decided to continue the voriconazole therapy. Four months later, he presented with a rapidly growing, indurated and centrally ulcerated cutaneous lesion in the right temporal region with a diameter of 22 mm (Figure 1). Local excision was performed. Histopathologic examination showed a poorly differentiated squamous cell carcinoma (SCC) with perineural invasion and strong expression of cytokeratin CK14. At the surface, residual bowenoid actinic keratosis was focally present (Figure 2). Four months following original excision, a local recurrence was diagnosed, with metastatic lymph nodes in the parotid gland. Because of his immunosuppressive therapy, it was decided to perform a regional (level I-III) lymphadenectomy, in addition to a wide excision of the cutaneous recurrence and a superficial parotidectomy. Several new-onset actinic keratoses on the face were also removed, voriconazole was discontinued and local radiotherapy on the temporal and parotid region was started. Histological examination did not show further metastatic localizations in the neck lymph nodes. Until now, neither recurrence nor new skin lesions occurred (follow-up period of 6 months).Figure 2Histologic examination of the right temporal lesion. The lesion arises from the epidermis and is composed of variably sized tumoral nasts. The arrows indicate residual bowenoid actinic keratosis (HE, × 100).View Large Image Figure ViewerDownload Hi-res image Download (PPT) In the past, the nephrotoxicity of conventional amphotericin B (which was essentially the only available drug for treating systemic mycoses until the late 1980s) was an important limiting factor in considering patients with a history of invasive aspergillosis for renal transplantation (1Sawaya BP Briggs JP Amphotericin B nephrotoxicity: The adverse consequences of altered membrane properties.J Am Soc Nephrol. 1995; 6: 154-164Crossref PubMed Google Scholar,2Harbarth S Pestotnik SL Lloyd JF Burke JP Samore MH The epidemiology of nephrotoxicity associated with conventional amphotericin B therapy.Am J Med. 2001; 111: 528Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). Since the mid-1990s, the efficacy of liposomal amphotericin B (3Carlini A Angelini D Burrows L De Quirico G Antonelli A Cerebral aspergillosis: Long-term efficacy and safety of liposomal amphotericin B in kidney transplant.Nephrol Dial Transplant. 1998; 13: 1659-2661Crossref Scopus (16) Google Scholar), new extended spectrum triazoles (voriconazole and posaconazole) and echinocandin antifungals (such as caspofungin) in treating invasive aspergillosis was proven (4Kauffman CA Clinical efficacy of new antifungal agents.Curr Opin Microbiol. 2006; 9: 483-488Crossref PubMed Scopus (53) Google Scholar,5Spanakis EK Aperis G Mylonakis E New agents for the treatment of fungal infections: Clinical efficacy and gaps in coverage.Clin Infect Dis. 2006; 43: 1060-1068Crossref PubMed Scopus (142) Google Scholar). Voriconazole has even become the drug of choice since a large multi-national randomized trial in 2002 that compared amphotericin B with voriconazole in 277 patients with proven or probable invasive aspergillosis, proved significantly more complete or partial responses and a higher patient survival in the group with voriconazole (6Herbrecht R Denning DW Patterson TF et al.Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.N Engl J Med. 2002; 347: 408-415Crossref PubMed Scopus (2840) Google Scholar). Moreover, these new treatments are less toxic (especially nephrotoxic) than conventional amphotericin B. These factors made it easier to consider a patient suitable for renal transplantation with a history of invasive aspergillosis but without clinical, radiographic or biochemical signs of active infection or colonization. And, because no recurrence of (invasive) aspergillosis has been noted during a 2-year follow-up period, it seems that solid organ transplantation could be performed safely in this patient with a history of invasive aspergillosis under antifungal profylaxis of voriconazole. However, dermatological complications have been associated with voriconazole therapy in 8.6% of patients in an open, noncomparative study (7Denning DW Ribaud P Milpied N et al.Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis.Clin Infect Dis. 2002; 34: 563-571Crossref PubMed Scopus (794) Google Scholar). Most common are mild skin rashes, but also phototoxic reactions, including erythema, cheilitis, hyperpigmentation of the hands, exfoliative dermatitis, discoid erythematous lesions, pseudoporphyria and discoid lupus vulgaris are reported (8Johnson LB Kauffman CA Voriconazole: A new triazole antifungal agent.Clin Infect Dis. 2003; 36: 630-637Crossref PubMed Scopus (666) Google Scholar, 9Rubenstein M Levy ML Metry D Voriconazole-induced retinoid-like photosensitivity in children.Pediatr Dermatol. 2004; 21: 675-678Crossref PubMed Scopus (50) Google Scholar, 10Denning DW Griffiths CEM Muco-cutaneous retinoid-effects and facial erythema related to the novel triazole antifungal agent voriconazole.Clin Exp Dermatol. 2001; 26: 648-653Crossref PubMed Scopus (121) Google Scholar, 11Vandecasteele SJ Van Wijngaerden E Peetermans WE Two cases of severe phototoxic reactions related to long-term outpatient treatment with voriconazole.Eur J Clin Microbiol Infect Dis. 2004; 23: 656-657Crossref PubMed Scopus (29) Google Scholar). The mechanism of voriconazole-induced phototoxicity (that seems to be idiosyncratic rather than dose-dependent) remains uncertain. One reasonable hypothesis is that voriconazole inhibits a step in the metabolic breakdown of all-trans retinol (vitamin A) leading to an increase in plasma levels of certain retinoids. Another plausible hypothesis is that voriconazole or one of its metabolites has the ability to elicit a phototoxic reaction (10Denning DW Griffiths CEM Muco-cutaneous retinoid-effects and facial erythema related to the novel triazole antifungal agent voriconazole.Clin Exp Dermatol. 2001; 26: 648-653Crossref PubMed Scopus (121) Google Scholar). At this moment, a pilot study is underway to determine potential genetic profiles in patients with voriconazole-induced phototoxicity (12National Cancer Institute [homepage on the internet]. National Cancer Institute, Inc., Bethesda. Available from: http://www.cancer.gov/clinicaltrials/NCI-06-C-0198 [updated 2007 Oct 7], Accessed October 22, 2007.Google Scholar). Prolonged voriconazole treatment complicated with phototoxicity has been associated with solar elastic changes, multiple lentigines and ephelides. Recently, the association has been suggested between prolonged voriconazole therapy when complicated with severe phototoxicity and the development of multi-focal invasive SCC, particularly in the context of significant ultraviolet exposure (13McCarthy KL Playford EG Looke DF Whitby M Severe photosensitivity causing multifocal squamous cell carcinomas secondary to prolonged voriconazole therapy.Clin Infect Dis. 2007; 44: e55-e56Crossref PubMed Scopus (92) Google Scholar). Although the patient described in this manuscript already had a high predisposition for skin malignancies because of long periods of intensive sun exposition of head and hands (he worked for decades in the Middle East) and because of immunosuppressive therapy before and after transplantation, there are some factors suggesting that voriconazole may have contributed to the development of this aggressive SCC. There is the temporary association of the phototoxic reaction and the synchronic onset of multiple actinic keratoses, but the most important factor is the abrupt onset and speed of growing as well as the aggressive nature of the SCC lesion (histological as well as anatomical). In our patient, the SCC lesion occurs 19 months after transplantation, while several studies demonstrate that SCC is not commonly diagnosed less than 5 years after transplantation (14Ramsay HM Reece SM Fryer AA Smith AG Harden PN Seven-year prospective study of nonmelanoma skin cancer incidence in U.K. renal transplant recipients.Transplantation. 2007; 84: 437-439Crossref PubMed Scopus (59) Google Scholar, 15Carroll RP Ramsay HM Fryer AA Hawley CM Nicol DL Harden PN Incidence and prediction of nonmelanoma skin cancer post-renal transplantation: A prospective study in Queensland, Australia.Am J Kidney Dis. 2003; 41: 676-683Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 16Moloney FJ Comber H O’Lorcain P O’Kelly P Conlon PJ Murphy GM A population-based study of skin cancer incidence and prevalence in renal transplant recipients.Br J Dermatol. 2006; 154: 498-504Crossref PubMed Scopus (370) Google Scholar). Another argument is the fact that after the discontinuation of voriconazole, no new skin lesions developed. Recent studies demonstrated that posaconazole (an extended spectrum triazole) is an alternative for patients with invasive aspergillosis who are refractory or intolerant to conventional antifungal therapy. Therefore, in patients with phototoxic reactions secondary to voriconazole treatment or patients at high-risk for the development of cutaneous malignancies (fair skin type, advanced age, significant ultraviolet exposure in the history and/or immunosuppressive therapy), posaconazole might be a useful salvage option (17Cornely OA Maertens J Winston DJ et al.Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia.N Engl J Med. 2007; 356: 348-359Crossref PubMed Scopus (1410) Google Scholar,18Walsh TJ Raad I Patterson TF et al.Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: An externally controlled trial.Clin Infect Dis. 2007; 44: 2-12Crossref PubMed Scopus (653) Google Scholar). In patients at high risk for the development of cutaneous malignancies, primary prevention including the avoidance of sun exposure, use of protective clothing and use of an effective sunscreen (protection factor >15) for unclothed body parts (head, neck, hands and arms) is also very important (19EBPG Expert Group on Renal TransplantationEuropean best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.2. Cancer risk after renal transplantation. Skin cancers: Prevention and treatment.Nephrol Dial Transplant. 2002; 17: 31-36Google Scholar). Although several studies suggests that retinoids may be beneficial in the treatment and/or prevention in nonmelanoma skin tumors after solid organ transplantation, systemic administration is not routinely performed because of potential toxic (headaches, mucocutaneous side effects, musculoskeletal symptoms and hyperlipidemia) and/or immunomodulatory effects. However in recipients with multiple and/or recurrent skin cancers, the use of systemic retinoids, such as low-dose acitretin, could be advised for months/years, if well tolerated (20Kovach BT Sams HH Stasko T Systemic strategies for chemoprevention of skin cancers in transplant recipients.Clin Transplant. 2005; 19: 726-734Crossref PubMed Scopus (58) Google Scholar, 21Carneiro RV Sotto MN Azevedo LS Ianhez LE Rivitti EA Acitretin and skin cancer in kidney transplanted patients. Clinical and histological evaluation and immunohistochemical analysis of lymphocytes, natural killer cells and Langerhans’ cells in sun exposed and sun protected skin.Clin Transplant. 2005; 19: 115-121Crossref PubMed Scopus (30) Google Scholar, 22Chen K Craig JC Shumack S Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: A systemic review of randomized controlled trials.Br J Dermatol. 2005; 152: 518-523Crossref PubMed Scopus (98) Google Scholar). In immunocompromised patients with the initial presentation of aggressive SCCs, Mohs micrographic surgery should be administered in order to minimize the risk of recurrence (23Neville JA Welch E Leffell DJ Management of nonmelanoma skin cancer in 2007.Nat Clin Pract Oncol. 2007; 4: 462-469Crossref PubMed Scopus (215) Google Scholar). It can be concluded that while a history of invasive aspergillosis is not an absolute contra-indication for solid organ transplantation, prolonged and adequate antifungal prophylaxis after transplantation seems indicated. The advent of new broad spectrum and low toxicity antifungal agents like voriconazole are very promising in this indication; however, caution is needed with new drug therapies. The development of aggressive squamous cell carcinoma associated with prolonged voriconazole therapy, especially in predisposed patients (significant ultraviolet exposure, immunosuppressive therapy, phototoxicity reaction), might be clinically important. Therefore, we feel obliged to inform the transplant community that primary prevention (application of total sunblock and sun-avoidance measures) and careful monitoring of skin lesions is needed in solid organ transplant patients during prolonged administration of voriconazole." @default.
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• W2018889597 title "Aggressive Cutaneous Squamous Cell Carcinoma Associated with Prolonged Voriconazole Therapy in a Renal Transplant Patient" @default.
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