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Research Updates

Skin Cancer in Solid-Organ Transplant Patient

Yevgeniy Balagula, Manisha Patel

Monday, December 01, 2014

Continued advances in solid-organ transplantation have improved long-term mortality among transplant patients.1 More than 140,000 organ recipients are living in the United States (US), with a similar number of patients on a waiting list.1 However, transplantation and iatrogenic immunosuppression are associated with adverse events and impact on morbidity, mortality, and patients' quality of life. While there is an overall increased risk of malignancy, skin cancers and particularly non-melanoma skin cancers (NMSCs) are most frequently observed (Figures 1 and 2).2-4 The risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) is 10 and 65 times greater compared to non-transplant patients, respectively.5 Importantly, the ratio of BCC to SCC is reversed among Caucasian patients, ranging from 1:1.2 to 1:15.5-9 The rate of melanoma among renal transplants is also 3.6 times greater compared to immunocompetent patients.10 Kaposi's sarcoma accounted for 79% of cancers among non-White patients in South Africa observed over a mean follow-up period of 6.3 years.11

 

Figure 1

Figure 1. Squamous cell carcinoma

 Figure 2

Figure 2. Keratoacanthoma

 

With the exception of Kaposi's sarcoma, a significant amount of data on incidence of NMSCs and melanoma has been derived from predominately Caucasian populations in European countries, Australia, and the US.12-19 In contrast, limited information addressing the extent and types of cutaneous malignancies in transplant patients with ethnic skin has been published thus far. One study showed a statistically significant decrease in 3-year cumulative incidence of NMSC in African American (AA) and Asian renal recipients as compared to Caucasians, with a relative risk of 0.06 and 0.11, respectively.20 A 10-year retrospective analysis of 6271 heart-transplant patients from 32 US transplant centers demonstrated an extremely low incidence of skin cancer among non-Caucasian patients (AA, Hispanic, Middle Eastern, Indian, Asian and Native American), which accounted for 15% of the study population.15 A 10-year period free of cancer among this non-Caucasian population was 99.2%.15 This data may become clinically important since it has been estimated that Hispanics, Asians and blacks will make up 50% of the US population by the year 2050.21

 

After the first NMSC, up to 80% of transplant patients will develop second primary NMSC within 3 years.16,22,23 Furthermore, the risk of developing NMSC is cumulative after the transplant and gradually increases with time.1 The degree of immunosuppression is also an important risk factor. Heart and lung transplant patients, who require higher levels of immunosuppression, have an increased propensity to develop NMSC as compared to renal and liver transplants.1

 

Fitzpatrick Skin Phototype (SPT) is an independent risk factor for NMSC development.24-27 The most recent study showed the cumulative incidence of SCC at 10 years to be 51% in patients with SPT I and 8% in SPT VI.24 Non-Caucasians constituted less than 8% of the study sample including only 11 (1.6%) AA and 26 (3.8%) Hispanic patients. Of note, no SCCs were observed among AA and four SCCs were diagnosed in Hispanic patients. This study also highlighted an important concept of wide variation of SPT within a particular ethnic group. The contribution of ultraviolet (UV) light to NMSC development is highlighted by its greater incidence in transplant patients in Australia as compared to other Western countries.14 UV-related risk factors in the post-transplant period include sunburn as a child, Fitzpatrick SPTs I through III, residing in a hot climate for more than 30 years, and significant prior UV exposure.28,29 Voriconazole, which has potent photosensitizing properties, is a potential contributing factor. In lung-transplant patients, duration of voriconazole therapy was an independent risk factor for developing SCC, which can have a more aggressive behavior.29 While the role of human papillomavirus (HPV) in SCC pathogenesis has not been entirely elucidated, several studies suggest its potential role. Transplanted patients harbor a greater quantity of various HPVs - particularly the beta type.1,30 Moreover, seropositivity to beta-type HPV37 was associated with significantly increased risk of SCC in the post-transplant period (odds ratio 2.0, 95% confidence interval 1.2-3.4).31 Additionally, three genetic variants of TMC8, the gene associated with epidermodysplasia verruciformis and predisposition to development of numerous warts and SCCs, were associated with greater seropositivity to two species of beta HPV viruses.31

 

Significant impairment of cutaneous immunosurveillance has been suspected to be the main culprit for the propensity to develop multiple NMSCs and SCC in particular.32,33 However, more light has been shed on the direct effect of immunosuppressive drugs, irrespective of their immunosuppressive properties. Cyclosporine diminishes the expression of tumor suppressor PTEN and UVB-induced DNA repair, thereby facilitating UVB-driven carcinogenesis. Similarly, in in vitro cell-culture, tacrolimus and mycophenolate mofetil also inhibit UVB-induced repair of cyclobutane pyrimidine dimers. Both immunosuppressant drugs also inhibit UVB-induced apoptosis, which serves as a major checkpoint in preventing uninhibited proliferation of keratinocytes.34 Azathioprine causes oxidative DNA damage in conjunction with UVA light.35

 

Thus far, there has been a lack of effective and consistent management strategies for patients with numerous NMSCs. Pre-emptive, frequent patient monitoring with surgical or non-surgical interventions is the current mainstay of treatment. However, besides reduction of immunosuppression, few systemic agents diminish the overall tumor burden. Mammalian target of rapamycin (mTOR) inhibitors are potentially helpful in reducing the development of SCCs. Five prospective clinical trials highlighted the ability of sirolimus to diminish the incidence of NMSC.36 Earlier transition to mTOR inhibitor-based immunosuppressive regimen may be more chemopreventative.37 Two large, randomized controlled clinical trials showed significant reduction of NMSC incidence in those patients who were switched to an mTOR inhibitor after their first NMSC.28,38,39 However, there is considerable incidence of side effects with up to 40% of patients discontinuing mTOR inhibitors, which limits its use.36

 

Further research efforts are needed to better understand the underlying pathophysiology of NMSCs in this patient population and to identify potential targets for prevention and treatment. In the interim, patient education and continued close surveillance are essential aspects of patient management (Figure 3). 

 

 

 Figure 3

Figure 3. Approach to history and physical exam of a new solid-organ transplant patient

 

 

 

References

  1. Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011 Aug;65(2):253-61; quiz 62.
  2. London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP. Risk of neoplasia in renal transplant patients. Lancet. 1995 Aug 12;346(8972):403-6.
  3. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003 Apr 24;348(17):1681-91.
  4. Penn I. Tumors after renal and cardiac transplantation. Hematol Oncol Clin North Am. 1993 Apr;7(2):431-45.
  5. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002 Jul;47(1):1-17; quiz 8-20.
  6. Gupta AK, Cardella CJ, Haberman HF. Cutaneous malignant neoplasms in patients with renal transplants. Arch Dermatol. 1986 Nov;122(11):1288-93.
  7. Penn I. Skin disorders in organ transplant recipients. External anogenital lesions. Arch Dermatol. 1997 Feb;133(2):221-3.
  8. Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl. 1994:99-109.
  9. Bourke JF, Mellott GJ, Young M, Donohoe J, Carmody M, Keogh JA. Skin cancer in an Irish renal transplant population. Ir J Med Sci. 1992 Apr;161(4):116-7.
  10. Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Lengerich EJ. Increased incidence of melanoma in renal transplantation recipients. Cancer. 2005 Nov 1;104(9):1962-7.
  11. Moosa MR. Racial and ethnic variations in incidence and pattern of malignancies after kidney transplantation. Medicine (Baltimore). 2005 Jan;84(1):12-22.
  12. Jensen AO, Svaerke C, Farkas D, Pedersen L, Kragballe K, Sorensen HT. Skin cancer risk among solid organ recipients: a nationwide cohort study in Denmark. Acta Derm Venereol. 2010 Sep;90(5):474-
  13. Jensen P, Hansen S, Moller B, Leivestad T, Pfeffer P, Geiran O, 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.
  14. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Harden PN. Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol. 2002 Nov;147(5):950-6.
  15. M, Brown RN, Silber DH, Mullen GM, Feldman DS, Oren RM, et al. Increased incidence and mortality associated with skin cancers after cardiac transplant. Am J Transplant. 2011 Jul;11(7):1488-97.
  16. Tessari G, Naldi L, Boschiero L, Nacchia F, Fior F, Forni A, et al. Incidence and clinical predictors of a subsequent nonmelanoma skin cancer in solid organ transplant recipients with a first nonmelanoma skin cancer: a multicenter cohort study. Arch Dermatol. 2010 Mar;146(3):294-9.
  17. Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol. 1999 Jan;40(1):27-34.
  18. Naldi L, Fortina AB, Lovati S, Barba A, Gotti E, Tessari G, et al. Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study. Transplantation. 2000 Nov 27;70(10):1479-84.
  19. Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN. Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients. Am J Kidney Dis. 2000 Jul;36(1):167-76.
  20. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant. 2004 Jun;4(6):905-13.
  21. Gloster HM, Jr., Neal K. Skin cancer in skin of color. J Am Acad Dermatol. 2006 Nov;55(5):741-60; quiz 61-4.
  22. Wisgerhof HC, Edelbroek JR, de Fijter JW et al. Subsequent squamous- and basal-cell carcinomas in kidney-transplant recipients after the first skin cancer: cumulative incidence and risk factors. Transplantation. 2010 May 27;89(10):1231-8.
  23. Euvrard S1, Kanitakis J, Decullier E et al. Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma. Transplantation. 2006 Apr 27;81(8):1093-100.
  24. Gogia R, Binstock M, Hirose R, Boscardin WJ, Chren MM, Arron ST. Fitzpatrick skin phototype is an independent predictor of squamous cell carcinoma risk after solid organ transplantation. J Am Acad Dermatol. 2013 Apr;68(4):585-91.
  25. Caforio AL, Fortina AB, Piaserico S, Alaibac M, Tona F, Feltrin G, 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.
  26. Espana A, Martinez-Gonzalez MA, Garcia-Granero M, Sanchez-Carpintero I, Rabago G, Herreros J. A prospective study of incident nonmelanoma skin cancer in heart transplant recipients. J Invest Dermatol. 2000 Dec;115(6):1158-60.
  27. Fortina AB, Caforio AL, Piaserico S, Alaibac M, Tona F, Feltrin G, et al. Skin cancer in heart transplant recipients: frequency and risk factor analysis. J Heart Lung Transplant. 2000 Mar;19(3):249-
  28. Hanlon A, Colegio OR. The cutting edge of skin cancer in transplant recipients: scientific retreat of international transplant Skin Cancer Collaborative and Skin Cancer in Organ Transplant Patients Europe. Am J Transplant. 2014 May;14(5):1012-5.
  29. Williams K1, Mansh M, Chin-Hong P et al. Voriconazole-associated cutaneous malignancy: a literature review on photocarcinogenesis in organ transplant recipients. Clin Infect Dis. 2014 Apr;58(7):997-1002.
  30. Ally MS1, Tang JY, Arron ST. Cutaneous human papillomavirus infection and Basal cell carcinoma of the skin. J Invest Dermatol. 2013 Jun;133(6):1456-8.
  31. Madeleine MM1, Carter JJ, Johnson LG et al. Risk of squamous cell skin cancer after organ transplant associated with antibodies to cutaneous papillomaviruses, polyomaviruses, and TMC6/8 (EVER1/2) variants. Cancer Med. 2014 Jun 10.
  32. Muehleisen B1, Jiang SB, Gladsjo JA et al. Distinct innate immune gene expression profiles in non-melanoma skin cancer of immunocompetent and immunosuppressed patients. PLoS One. 2012;7(7):e40754.
  33. Hampton T. Skin cancer's ranks rise: immunosuppression to blame. JAMA. 2005 Sep 28;294(12):1476-80.
  34. Ming M, Zhao B, Qiang L et al. Effect of Immunosuppressants Tacrolimus and Mycophenolate Mofetil on the Keratinocyte UVB Response. Photochem Photobiol. 2014 Jul 21.
  35. O'Donovan P1, Perrett CM, Zhang X et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 2005 Sep 16;309(5742):1871-4.
  36. Alter M1, Satzger I, Schrem H et al. Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR-inhibitors in organ transplant recipients. J Dtsch Dermatol Ges. 2014 Jun;12(6):480-8.
  37. Colegio OR1, Hanlon A, Olasz EB et al. Sirolimus reduces cutaneous squamous cell carcinomas in transplantation recipients. J Clin Oncol. 2013 Sep 10;31(26):3297-8.
  38. Euvrard S, Morelon E, Rostaing L et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012 Jul 26;367(4):329-39.
  39. Hoogendijk-van den Akker JM1, Harden PN, Hoitsma AJ et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J Clin Oncol. 2013 Apr 1;31(10):1317-23.

 

 

 

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