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Reducing Skin Malignancy Risk in Organ Transplant Recipients

Shayla Francis, MD and Daniel Berg, MD
Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA, USA

ABSTRACT

Skin cancer in organ transplant recipients is a serious problem that manifests as increased squamous cell carcinoma in longterm patients. In these patients, a combination of cumulative sun exposure as well as the immunosuppressive effects of transplant medications can cause cutaneous malignancy. Skin cancer can affect transplant patients in multiple ways. It can decrease quality of life by causing various separate skin cancers that require frequent and sometimes painful treatment, as well as possibly result in disfigurement. The more aggressive tumors pose a risk of metastasis and death. Clinical efforts aimed at reduction in skin cancers in this high-risk population include increased education and surveillance, aggressive treatment of skin cancers and pre-cancers, changes to immunosuppressive regimens, and retinoid chemoprevention.

Key Words: chemoprevention, cutaneous neoplasms, immunosuppression, organ transplantation, retinoids, skin cancer

Background

Skin cancer in transplant recipients poses a unique challenge to physicians and patients alike. Both skin cancer aggressiveness and incidence are increased in organ transplant recipients, with a 65-fold increase in squamous cell carcinoma in long-term patients compared to baseline.1 In addition to the affects that skin cancer can have on quality of life, it can also be life threatening, as evidenced in Australia where skin cancer is responsible for 27% of deaths in heart transplant patients after the fourth posttransplant year.2 Survival after transplantation has steadily increased with the 1- and 5-year survival rates of 83% and 75%, respectively, for liver transplant patients, and even higher survival rates for kidney transplant recipients.3 The increasing survival rates result in a sizable group of transplant patients at risk for the long-term complications of chronic immunosuppression including cutaneous malignancy.

Immunosupressive medications can inhibit the immune system's ability to fight malignant cells and oncogenic viruses. Some immunosuppressive drugs may have a direct oncogenic effect. Not unexpectedly, studies have demonstrated that transplant recipients have an increased risk of cutaneous squamous cell carcinoma (SCC) (65-fold), malignant melanoma (3-fold), and Kaposi's sarcoma (84-fold), when compared with the general population.4 Optimal management of this patient population requires a proactive approach tailored to each individual's risk factors and needs.

Identification of High-risk Patients and Lesions

The potential for highly aggressive skin cancers in immunosuppressed patients highlights the need for early diagnosis prior to any potential spread of the lesions. Recommendations by the American Society of Transplantation suggest that all renal transplant patients perform monthly self skin examinations and annual skin examinations by a physician.5

These recommendations are inadequate in higher risk transplant patients where skin cancers occur more frequently.6 The identification of patients at higher risk helps individualize screening and therapy. Factors that increase risk of skin cancer include longer time post-transplant (duration of immunosuppression), intensity of immunosuppression, age at time of transplant, extent of sun exposure, presence of human papilloma virus (HPV) infection, Fitzpatrick types I-III skin, history of skin cancer prior to transplant, and CD4 lymphopenia.7-9 Skin cancer examination follow-up interval depends on the severity of prior disease and the presence of other risk factors, but can range from once annually to as often as once every 4-8 weeks.

Patient education is critical and patients should be informed about aggressive sun protection and their higher risk of skin cancer. One survey of renal transplant patients demonstrated that 41% were unable to recall skin cancer education and only 14% had regular dermatologic follow-up.10 This study emphasizes that patient outreach with clarity and repetition in the message of sun protection and screening is needed in order to be effective.

Regular surveillance by a dermatologist should be recommended for all patients at high risk of skin cancer. Monthly self skin examination looking for changes that would be concerning for malignancy should be encouraged. Following a squamous cell carcinoma with high-risk factors (poorly differentiated, perineural invasion, large, and high-risk location) or melanoma, self lymph node examination should be emphasized and education should be included in post-op follow-up visits.

The efficacy of education regarding the use of sunscreen in transplant patients was explored by Ulrich et al.11 The investigators demonstrated that organ transplant patients (kidney, liver, and heart) with actinic keratoses (AKs) who used sunscreen for an average 5-6 applications per week, in addition to receiving counseling in sun protective behavior, had reduced AK and non-melanoma skin cancers (NMSC) compared to those counseled about sun protection alone. These findings and other similar studies in other patient populations highlight the value of education about regular sunscreen use in skin cancer prevention.

Aggressive Traditional Treatments

Evaluation of severely sun damaged skin can be challenging. Treatment of pre-cancerous sun damage should be aggressive. The treatments are varied and include cryotherapy, 5-fluorouracil cream, topical non-steroidal anti-inflammatories, topical ingenol mebutate, retinoids, photodynamic therapy, or imiquimod. The objective of early skin cancer treatment is to reduce rates of NMSC and improve quality of life. SCCs and hyperkeratotic AK may appear clinically similar and the threshold for biopsy should be low to tailor the therapy accordingly.

Transplant patients can have aggressive and life threatening tumors and therefore invasive malignancy should be treated as such. SCC in transplant patients has an increased chance of local, regional or systemic metastases. By way of example, one study reported that of 6596 patients, 1293 (20%) were found to have skin cancer. Of those patients, 7% developed metastasis and 5% of those with SCC died from the cancer.12 The rates of NMSC metastasis for the general population range from 0.01% to 0.1%.13

Individual skin cancers can be managed with standard techniques. These include electrodesiccation and curettage, excision, Mohs micrographic surgery for high-risk skin cancer on the head and neck, and radiation in poor surgical candidates. Close clinical follow-up should always be undertaken when destructive methods are used and clear margins are not confirmed. All melanomas and SCCs should be treated both aggressively and in a timely fashion following identification of the malignancy.

Immunosuppressive Medications

The immunosuppressive regimen used in a transplant patient can affect the development of cutaneous malignancy. Both clinical observation and albino mouse models have shown that patients treated with azathioprine may be at higher risk for skin cancer development, whereas oral steroids confer the lowest risk for skin cancer. Evidence is lacking in human trials to define the hierarchy of skin cancer risk amongst agents, but some have suggested that tacrolimus may be lower risk than cyclosporine and mycophenolate mofetil may be lower risk than azathioprine. Other studies argue these findings.14

Patients treated with higher levels of immunosuppression immediately after transplant and those who are on more immunosuppressive medications have a higher incidence of skin cancer.1,7,15 Immunosuppressive therapy with three drug regimens confer higher risk for skin cancer than two drug regimens.16 This suggests that a reduction in immunosuppression or change in choice of immunosuppressive drugs and regimens may be effective in reducing transplant-related skin cancer. Other evidence supports this theory.17 One randomized controlled trial showed that reduction in cyclosporine dosage in renal transplant patients resulted in a reduction in skin cancer without an increase in organ rejection.18 A recent survey of transplant physicians and dermatologists found that most felt a reduction of immunosuppression was warranted in cases of multiple or highrisk skin cancers.19

Sirolimus (rapamycin) and everolimus are kinase inhibitors that interfere with m-TOR, a key target in angiogenesis and cell proliferation. These agents are anti-angiogenic and antineoplastic20 and have gained attention for their anti-neoplastic effect in transplant patients who are at high risk for skin cancer. A retrospective United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) review demonstrated a 60% reduced risk of any post-transplant malignancy.21 Sirolimus is uncommonly used at the time of transplant due to issues with graft survival and wound healing, but may be considered farther out from transplant in select patients.22

Retinoid Chemoprevention

Vitamin A derivatives such as acitretin and isotretinoin have been used as chemopreventive agents. A small double-blind, placebo-controlled study demonstrated that a 6 month course of acitretin resulted in reduced NMSC in renal transplant patients.23 A second study found acitretin administered daily for 5 years had a more dramatic reduction in NMSC in patients with a history of five or more tumors.24

Systemic retinoid therapy for chemoprevention should be considered when a transplant patient experiences significant decreased quality of life from multiple skin cancers or when faced with cutaneous malignancies at high risk of metastasis. When a patient meets this threshold, discussion with the transplant physicians and patient about reduction or change of immunosuppression regimens should be considered.

Both response and side effects of retinoid therapy are dose dependent. Starting with a low dose and slowly advancing the therapy appears to increase patient tolerance of the adverse effects. Education regarding early use of emollients can be advantageous.25 A low dose regimen can consist of acitretin 10 mg/day (or 10 mg every other day), advancing by 10 mg increments at 2-4 week intervals as tolerated and needed. Because treatment tolerability varies among patients, 10-15 mg/day every other day or 3 times weekly dosing may be helpful in those who cannot tolerate the 20-25 mg/day recommended dose. Tolerance is a risk in those on long-term therapy and many rebound after cessation of the drug.

Side effects are mild and include mucocutaneous effects (e.g., cheilitis and dryness of the mucous membranes), alopecia, and elevation of triglycerides, liver function tests, and cholesterol. Although the data is largely lacking, these medications are not thought to reduce transplant organ function. Acitretin has a long half-life and pregnancy must be avoided for 3 years after therapy. If use of an oral retinoid in a female patient of child-bearing potential is necessary, consider isotretinoin because pregnancy must only be avoided for at least 1 month after stopping the drug. No retinoid therapy is US FDA approved for skin cancer chemoprevention and all must be used off-label.

Close clinical follow-up is important early in the initiation of retinoid therapy and a history and physical examination should be part of a baseline exam in conjunction with focused lab studies. Lab studies should include initial fasting lipids, liver function tests, hepatitis panel, creatinine, glucose, urine analysis, and complete blood count. Fasting lipids, liver function tests, and creatinine should be followed monthly until stable, then at least every 3 months through the duration of therapy. Bone density measurements should be considered but are frequently done by the primary transplant physician.

Other Agents to Consider in Prophylaxis

Capecitabine is an oral prodrug of 5-fluorouracil. It is used in advanced gastrointestinal cancer as a maintenance therapy in lower doses. A recent study has suggested it may significantly reduce the incidence of SCC and AK in organ transplant recipients. One-third of patients discontinued the drug at 1 year and the study was retrospective with a small sample size. Nevertheless, it may provide an additional chemopreventative approach.25

Given the success of HPV vaccination at reducing cervical cancer, the possibility has been raised of HPV vaccination being an effective secondary prevention tool in iatrogenically immunosuppressed patients such as organ transplant recipients. Although the HPV serotypes found in currently available vaccines are seen more commonly in cervical, head and neck, or digital skin cancers, there may be some role in the future for these or newer vaccines in organ transplant recipients.26

Conclusion

Skin cancer in organ transplant recipients is a source of increased morbidity and mortality. Multiple strategies are available to be used by the dermatologist involving surveillance, education, prophylaxis and treatment. As part of a multidisciplinary team caring for these patients, the knowledgeable dermatologist can have a significant impact.

References

  1. Jensen P, Moller B, Hansen S. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 2000 Feb;42(2 Pt 1):307.
  2. Ong CS, Keogh AM, Kossard S, et al. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol. 1999 Jan;40(1):27-34.
  3. Adam R, Hoti E. Liver transplantation: the current situation. Semin Liver Dis. 2009 Feb;29(1):3-18.
  4. 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 Feb;40(2 Pt 1):177-86.
  5. Kasiske BL, Vazquez MA, Harmon WE, et al. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol. 2000 Oct;11 Suppl 15:S1-86.
  6. Fuente MJ, Sabat M, Roca J, et al. A prospective study of the incidence of skin cancer and its risk factors in a Spanish Mediterranean population of kidney transplant recipients. Br J Dermatol. 2003 Dec;149(6):1221-6.
  7. Caforio AL, Fortina AB, Piaserico S, et al. Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy. Circulation. 2000 Nov 7; 102(19 Suppl 3):III222-7.
  8. Ducloux D, Carron PL, Rebibou JM, et al. CD4 lymphocytopenia as a risk factor for skin cancers in renal transplant recipients. Transplantation. 1998 May 15;65(9):1270-2.
  9. Lampros TD, Cobanoglu A, Parker F, et al. Squamous and basal cell carcinoma in heart transplant recipients. J Heart Lung Transplant. 1998 Jun;17(6):586-91.
  10. Cowen EW, Billingsley EM. Awareness of skin cancer by kidney transplant patients. J Am Acad Dermatol. 1999 May;40(5 Pt 1):697-701.
  11. 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, casecontrol study. Br J Dermatol. 2009 Nov;161 Suppl 3:78-84.
  12. Sheil AG, Disney AP, Mathew TH, et al. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc. 1993 Feb; 25(1 Pt 2):1383-4.
  13. Jemec GB, Holm EA. Nonmelanoma skin cancer in organ transplant patients. Transplantation. 2003 Feb 15;75(3):253-7.
  14. Kuschal C, Thoms KM, Schubert S, et al. Skin cancer in organ transplant recipients: effects of immunosuppressive medications on DNA repair. Exp Dermatol. 2012 Jan; 21(1):2-6.
  15. Bordea C, Wojnarowska F, Millard PR, et al. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation. 2004 Feb 27;77(4):574-9.
  16. Otley CC, Griffin MD, Charlton MR, et al. Reduction of immunosuppression for transplant-associated skin cancer: thresholds and risks. Br J Dermatol. 2007 Dec;157(6):1183-8.
  17. Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998 Feb 28;351(9103):623-8.
  18. Otley CC, Berg D, Ulrich C, et al. Reduction of immunosuppression for transplantassociated skin cancer: expert consensus survey. Br J Dermatol. 2006 Mar;154(3): 395-400.
  19. Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist. 2007 Aug;12(8):1007-18.
  20. Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 2005 Oct 15;80(7):883-9.
  21. Rostaing L, Kamar N. mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field? J Nephrol. 2010 Mar-Apr;23(2):133-42.
  22. 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 Aug;13(8):1933-8.
  23. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol. 1999 Apr;140(4):656-60.
  24. Otley CC, Stasko T, Tope WD, et al. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006 Apr;32(4):562-8.
  25. Jirakulaporn T, Endrizzi B, Lindgren B, et al. Capecitabine for skin cancer prevention in solid organ transplant recipients. Clin Transplant. 2011 Jul-Aug;25(4):541-8.
  26. Savani BN, Goodman S, Barrett AJ. Can routine posttransplant HPV vaccination prevent commonly occurring epithelial cancers after allogeneic stem cell transplantation? Clin Cancer Res. 2009 Apr 1;15(7):2219-21.

In this issue:

  1. Reducing Skin Malignancy Risk in Organ Transplant Recipients
  2. Urticaria and Angioedema: A Rational Approach to Diagnosis and Therapy
  3. Update on Drugs and Drug News - January 2013