By Susan O’Gorman, MD, and Gillian Murphy, MD
People who undergo organ transplants are living longer than ever, with some 250,000 patients alive in the US as of 2011.1 With improved survival, however, the increased risk of skin cancer in transplant patients has become ever more apparent.
The Problem: Immune Suppression
Transplant patients are given drugs such as cyclosporine and azathioprine to suppress their immune system so that it will not attack the donated organ as a foreign invader; the drugs enable the body to accept the organ. Unfortunately, immune-suppressed people, including recipients of all major solid organs (heart, lung, kidney, pancreas, liver), have a much higher risk of skin cancers than people in the general population.2-4 Squamous cell carcinoma (SCC), the second most common skin cancer, is the most frequent problem, occurring 65 to 250 times more often in transplant patients,5,6 but melanoma also occurs 6 to 8 times more7,8 frequently. Kaposi’s sarcoma, basal cell carcinoma (the most common skin cancer), and Merkel cell carcinoma (a virulent but normally very rare skin cancer) are also more common in transplant patients.
Pale skin, a key risk factor for skin cancer in the general population, is a far greater predisposing factor in transplant patients, especially after many years on immune suppressant drugs.9 For example, 36 percent of Irish renal (kidney) transplant recipients develop a nonmelanoma skin cancer 20 years after transplantation.10
A major reason for pale-skinned patients’ increased risk is their high vulnerability to sun damage. Lifetime exposure to ultraviolet (UV) radiation from either the sun or indoor UV tanning is a major risk factor in itself;11 UV radiation is a well-established cancer-causing agent that can independently start and sustain cancer development. About 90 percent of all nonmelanoma skin cancers are associated with UV radiation.12
Other important risk factors include the length of time the patient has been immunosuppressed;7,11,13-17 advancing age;7,9,11 male sex;7,9,11 human papillomavirus (HPV, or wart virus) infection, warts,18 and predisposing genetic variations (polymorphisms) such as the MC1R gene (the so-called red-headed gene) that lighten skin color and increase UV sensitivity, or those that reduce the body’s ability to repair UV damage, for example by disrupting folate metabolism19 [Table 1].
Just how much immunosuppressive drugs increase skin cancer risk depends on all of these factors, as well as the drugs themselves — azathioprine and calcineurin inhibitors such as tacrolimus, for example, may cause more cancers, while regimens revolving around mycophenolate mofetil or rapamycin may be lower risk, though data are insufficient to say any of this conclusively.2,11,13-16 In any event, patients may remain on several of these drugs for decades, and those taking three or four are more likely to develop skin cancer than those taking just two.7,17
The Impact of Viruses
Skin cancers associated with viruses that trigger tumor growth are seen at a far higher rate in immunosuppressed patients.20 There is increasing evidence implicating HPV in the development of squamous cell carcinomas, which can be especially aggressive in transplant patients.21-25 Similarly, the Merkel cell polyomavirus and human herpes virus (HHV)8, respectively, contribute to development of the dangerous skin cancers Merkel cell carcinoma and Kaposi’s sarcoma,26 which are likewise more common in the transplant population.
Though UV exposure is such an important skin cancer risk factor for transplant patients, it can be readily reduced. Following a transplant, patients must be exceptionally diligent about using sun protection. First and foremost, they need to seek the shade and avoid sun exposure when the sun is most intense, between 10 AM and 4 PM in temperate zones. This is true even on cloudy days, since UV rays pass through clouds.
If sun exposure is unavoidable, they should wear bright- or dark-colored, tightly woven or knit opaque clothing. Ideally, this should include long-sleeved shirts, long pants, a broad-brimmed hat, and wide-lensed wraparound UV- blocking sunglasses to cover as much skin as possible. For greater assurance, they can seek specially designed UV-protective clothes that display an ultraviolet protection factor (UPF) label, indicating their level of sun protection; clothes with a UPF of 50 or higher are needed for transplant patients.
Sunscreens can also help prevent the harmful effects of UV radiation, but their use should not lull patients into complacently believing they are fully protected; most people apply only 10–30 percent of the recommended amount (about two tablespoonfuls all over the body).27 Patients should opt for a broad-spectrum UVA/UVB sunscreen28 with an SPF factor of 50+, and frequently reapply it to exposed sites; this may compensate in part for the less- than-optimal quantity typically used.29 Sunscreen should be used even when you are driving, since the sun’s UVA rays pass abundantly through glass; an alternative is specialized window film that keeps UVA out.
One caution about carefully practicing sun protection is that sunlight is a major producer of vitamin D, and adequate levels of vitamin D are essential for bone health. Given the importance of sun safety for transplant patients, it is vital for them to be screened for vitamin D deficiency, and to seek out dietary sources and supplements for daily use.30
Transplant patients should examine their skin head to toe each month and see a dermatologist for a full-body skin exam at least every year, as it may aid in early detection of potentially deadly melanomas, aggressive SCCs, and other skin cancers.31-36 All skin cancers are more easily curable and cause less damage when found early. Furthermore, skin examination may detect skin precancers such as actinic keratoses (AKs) before they turn into cancers. This is especially relevant for transplant patients since SCCs often begin as AKs.
Preventative Treatment with Drugs (Chemoprevention)
The use of retinoids (vitamin A derivatives) to prevent skin cancers and precancers in transplant patients is well established, and it appears that one, acitretin, is particularly effective.37-41 The drug rapamycin (not a retinoid) also helps prevent skin cancers in transplant patients.42-44 Strategies to minimize skin cancer risk in organ transplant recipients are summarized in Table 2. For transplant patients who develop aggressive squamous cell carcinomas, which can be life-threatening, there is another option: lowering the immunosuppressant dose. Despite fears that this might wreak havoc with transplant patients’ immune systems, evidence suggests that it can improve the skin cancer prognosis without jeopardizing the transplant.45
Skin cancers are a serious risk for transplant patients, but with rigorous sun safety practices and the ongoing research of dedicated scientists, patients and doctors are increasingly well equipped to prevent, detect, and treat their skin cancers.
Susan O’Gorman, MD, is a Registrar in Dermatology to Dr. Gillian Murphy at Beaumont Hospital in Dublin, Ireland.
- Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2011 Annual Data report 6. Rockville, MD: Department of Health and Human Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation 2012; pp.13, 76, 123.
- Gerlini G, Romagnoli P, Pimpinelli N. Skin cancer and immunosup- pression. Crit Rev Oncol Hematol 2005; 56(1):127-36.
- Krynitz B, Edgren G, Lindelof B, et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008— a Swedish population-based study. Int J Cancer 2013; 132(6):1429-38. doi: 10.1002/ijc.27765. Epub 2012 Aug 28.
- SpanogleJP,KudvaYC,DierkhisingRA,etal.Skincancerafter pancreas transplantation. J Am Acad Dermatol 2012; 67(4):563-9.
- Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999; 40(2 Pt 1):177-86.
- Hartevelt MM, Bavinck JN, Kootte AM, et al. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 1990; 49(3):506-9.
- Moloney FJ, Comber H, O’Lorcain P, et al. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol 2006; 154(3):498-504.
- Le Mire L, Hollowood K, Gray D, et al. Melanomas in renal transplant recipients. Br J Dermatol 2006; 154(3):472-7.
- Keller B, Braathen LR, Marti HP, Hunger RE. Skin cancers in renal transplant recipients: a description of the renal transplant cohort in Bern. Swiss Med Wkly 2010; 140:w13036.
- Traynor C, Jenkinson A, Williams Y, et al. Twenty-year survivors of kidney transplantation. Am J Transplant 2012; 12(12):3289-95.
- Molina BD, Leiro MG, Pulpon LA, et al. Incidence and risk factors for nonmelanoma skin cancer after heart transplantation. Transplant Proc 2010; 42(8):3001-5.
- Koh HK, Geller AC, Miller DR, et al. Prevention and early detection strategies for melanoma and skin cancer: current status. Arch Dermatol 1996; 132:436-442.
- Wisgerhof HC, van der Boog PJ, de Fijter JW, et al. Increased risk of squamous-cell carcinoma in simultaneous pancreas kidney transplant recipients compared with kidney transplant recipients. J Invest Dermatol 2009; 129(12):2886-94.
- Navarro MD, Lopez-Andreu M, Rodriguez-Benot A, et al. Cancer incidence and survival in kidney transplant patients. Transplant Proc 2008; 40(9):2936-40.
- O’Neill JO, Edwards LB, Taylor DO. Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006; 25(10):1186-91.
- Crespo-Leiro MG, Alonso-Pulpon L, Vazquez de Prada JA, et al. Malignancy after heart transplantation: incidence, prognosis and risk factors. Am J Transplant 2008; 8(5):1031-9.
- Mackintosh LJ, Geddes CC, Herd RM. Skin tumours in the West of Scotland renal transplant population. Br J Dermatol 2012 Nov 8. doi: 10.1111/bjd.12129. [Epub ahead of print]
- Comeau S, Jensen L, Cockfield SM, et al. Non-melanoma skin cancer incidence and risk factors after kidney transplantation: a Canadian experience. Transplantation 2008; 86(4):535-41.
- Laing ME, Kay E, Conlon P, Murphy GM. Genetic factors as- sociated with skin cancer in renal transplant patients. Photodermatol Photoimmunol Photomed 2007; 23(2-3):62-67.
- Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370(9581):59-67.
- Shamanin V, zur Hausen H, Lavergne D, et al. Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients. J Natl Cancer Inst 1996; 88(12):802-11.
- Bouwes Bavinck JN, Euvrard S, Naldi L, et al. Keratotic skin lesions and other risk factors are associated with skin cancer in organ-transplant recipients: a case-control study in The Netherlands, United Kingdom, Germany, France, and Italy. J Invest Dermatol 2007; 127(7):1647-56.
- Meyer T, Arndt R, Nindl I, et al. Association of human papil- lomavirus infections with cutaneous tumors in immunosuppressed patients. Transpl Int 2003; 16(3):146-53.
- Stockfleth E, Nindl I, Sterry W, et al. Human papillomaviruses in transplant-associated skin cancers. Dermatol Surg 2004; 30(4 Pt 2):604-9.
- Harwood CA, Surentheran T, Sasieni P, et al. Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin. Br J Dermatol 2004; 150(5):949-57.
- Arron ST, Jennings L, Nindl I, et al. Viral oncogenesis and its role in nonmelanoma skin cancer. Br J Dermatol 2011; 164(6):1201-13.
- Autier P, Boniol M, Severi G, Doré JF. Quantity of sunscreen used by European students. Br J Dermatol 2001; 144(2):288-91.
- Moyal DD, Fourtanier AM. Broad-spectrum sunscreens provide better protection from solar ultraviolet-simulated radiation and natural sunlight-induced immunosuppression in human beings. J Am Acad Dermatol 2008; 58(5 Suppl 2):S149-54.
- Ou-Yang H, Stanfield J, Cole C, et al. High-SPF sunscreens (SPF >/= 70) may provide ultraviolet protection above minimal recommended levels by adequately compensating for lower sunscreen user application amounts. J Am Acad Dermatol 2012; 67(6):1220-7.
- Reichrath J. Dermatologic management, sun avoidance and vitamin D status in organ transplant recipients (OTR). J Photochem Photobiol B 2010; 101(2):150-9.
- Titus LJ, Clough-Gorr K, Mackenzie TA, et al. Recent skin self-examination and doctor visits in relation to melanoma risk and tumour depth. Br J Dermatol 2012; 168(3):571-6. doi: 10.1111/ bjd.12003. Epub 2012 Oct 5.
- Breitbart EW, Waldmann A, Nolte S, et al. Systematic skin cancer screening in Northern Germany. J Am Acad Dermatol 2012; 66:201-11.
- Mudigonda T, Levender MM, O’Neill JL, et al. Incidence, risk factors, and preventative management of skin cancers in organ transplant recipients: a review of single- and multicenter retrospective studies from 2006 to 2010. Dermatol Surg 2013; 39(3 Pt 1):345-64. doi: 10.1111/dsu.12028. Epub 2012 Nov 27.
- Ulrich C, Jurgensen JS, Degen A, et al. Prevention of non- melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study. Br J Dermatol 2009; 161 Suppl 3:78-84.
- Feuerstein I, Geller AC. Skin cancer education in transplant recipients. Prog Transplant 2008; 18(4):232-41; quiz 42.
- Tavadia S, Dawn G, Payne C, et al. Skin-cancer awareness in Scottish cardiac transplant recipients. Clin Exp Dermatol 2006; 31(3):354-7.
- Chen K, Craig JC, Shumack S. Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials. Br J Dermatol 2005; 152(3):518-23.
- George R, Weightman W, Russ GR, et al. Acitretin for che- moprevention of non-melanoma skin cancers in renal transplant recipients. Australas J Dermatol 2002; 43(4):269-73.
- Bouwes Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995; 13(8):1933-8.
- McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol 1999; 140(4):656-60.
- de Sevaux RG, Smit JV, de Jong EM, et al. Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin. J Am Acad Dermatol 2003; 49(3):407-12.
- McQuillan RF, O’Seaghdha CM, Bagatto A, et al. The effect of switching from calcineurin inhibitor to sirolimus on the incidence of skin cancers in kidney transplant recipients. J Eur Acad Dermatol Venereol 2009; 23(3):330-1.
- Alberu J, Pascoe MD, Campistol JM, et al. Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation 2011; 92(3):303-10.
- Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012; 367(4):329-39.
- Moloney FJ, Kelly PO, Kay EW, et al. Maintenance versus reduction of immunosuppression in renal transplant recipients with aggressive squamous cell carcinoma. Dermatol Surg 2004; 30(4 Pt 2):674-8.