Guarding against nonmelanoma skin cancer in solid organ transplant recipients

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doi:10.12788/jfp.0172

Applied Evidence

Guarding against nonmelanoma skin cancer in solid organ transplant recipients

J Fam Pract. 2021 April;70(3):121-130 | 10.12788/jfp.0172

By

Chance Morris, MD

Thomas Stasko, MD

Lindsey Collins, MD

Periodic skin examination and ongoing counseling are central in your posttransplantation care of these patients at high risk of skin malignancy.

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PRACTICE RECOMMENDATIONS

› Conduct a full-body skin examination at least once annually for solid organ transplant recipients. C

› Encourage daily use of broad-spectrum SPF ≥ 30 sunscreen and sun-protective clothing (long sleeves, pants, wide-brimmed hats) for these patients. A

› Consider chemoprophylactic agents for patients at especially high risk of nonmelanoma skin cancer. A

› Treat nonmelanoma skin cancer in a solid organ transplant recipient aggressively because of their increased risk of recurrence, local invasion, and metastasis. B

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

References

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18. Wu SZ, Jiang P, DeCaro JE, et al. A qualitative systematic review of the efficacy of sun protection education in organ transplant recipients. J Am Acad Dermatol. 2016;75:1238-1244.e5. doi: 10.1016/j.jaad.2016.06.031

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20. Urwin HR, Jones PW, Harden PN, et al. Predicting risk of nonmelanoma skin cancer and premalignant skin lesions in renal transplant recipients. Transplantation. 2009;87:1667-1671. doi: 10.1097/TP.0b013e3181a5ce2e

21. Infusino SD, Loi C, Ravaioli GM, et al. Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience. G Ital Dermatol Venereol. 2020;155:662-668. doi: 10.23736/S0392-0488.18.06091-1

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25. Puza CJ, Myers SA, Cardones AR, et al. The impact of transplant rejection on cutaneous squamous cell carcinoma in renal transplant recipients. Clin Exp Dermatol. 2018;44:265-269. doi: 10.1111/ced.13699

26. Abikhair Burgo M, Roudiani N, Chen J, et al. Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma. JCI Insight. 2018;3:e120750. doi: 10.1172/jci.insight.120750

27. Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: management of advanced and high-stage tumors. J Am Acad Dermatol. 2018;78:249-261. doi: 10.1016/j.jaad.2017.08.058

28. Askew DA, Mickan SM, Soyer HP, et al. Effectiveness of 5-fluorouracil treatment for actinic keratosis—a systematic review of randomized controlled trials. Int J Dermatol. 2009;48:453-463. doi: 10.1111/j.1365-4632.2009.04045.x

29. Salim A, Leman JA, McColl JH, et al. Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen‘s disease. Br J Dermatol. 2003;148:539-543. doi: 10.1046/j.1365-2133.2003.05033.x

30. Morton CA. A synthesis of the world‘s guidelines on photodynamic therapy for non-melanoma skin cancer. G Ital Dermatol Venereol. 2018;153:783-792. doi: 10.23736/S0392-0488.18.05896-0

31. Joly F, Deret S, Gamboa B, et al. Photodynamic therapy corrects abnormal cancer-associated gene expression observed in actinic keratosis lesions and induces a remodeling effect in photodamaged skin. J Dermatol Sci. 2018;S0923-1811(17)30775-2. doi: 10.1016/j.jdermsci.2018.05.002

32. Patel GK, Goodwin R, Chawla M, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen‘s disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2006;54:1025-1032. doi: 10.1016/j.jaad.2006.01.055

33. Imiquimod. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7077?cesid=aRo1Yh9sd0Q&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dimiquimod%26t%3Dname%26va%3Dimiquimod

34. Diclofenac. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6th, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/1772965?cesid=5vTk7J3Vmvc&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Ddiclofenac%26t%3Dname%26va%3Ddiclofenac

35. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618-1626. doi: 10.1056/NEJMoa1506197

36. Yiasemides E, Sivapirabu G, Halliday GM, et al. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis. 2009;30:101-105. doi: 10.1093/carcin/bgn248

37. 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;32:562-568. doi: 10.1111/j.1524-4725.2006.32115.x

38. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol. 1999;140:656-660. doi: 10.1046/j.1365-2133.1999.02765.x

39. Capecitabine. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed February 13, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6519?cesid=7WMsK72X7T7&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dcapecitabine%26t%3Dname%26va%3Dcapecitabine

40. Wollina U, Hansel G, Koch A, et al. Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin. J Cancer Res Clin Oncol. 2005;131:300-304. doi: 10.1007/s00432-004-0656-6

41. Zavattaro E, Veronese F, Landucci G, et al. Efficacy of topical imiquimod 3.75% in the treatment of actinic keratosis of the scalp in immunosuppressed patients: our case series. J Dermatol Treat. 2020;31:285-289. doi: 10.1080/09546634.2019.1590524

42. Neugebauer R, Su KA, Zhu Z, et al. Comparative effectiveness of treatment of actinic keratosis with topical fluorouracil and imiquimod in the prevention of keratinocyte carcinoma: a cohort study. J Am Acad Dermatol. 2019;80:998-1005. doi: 10.1016/j.jaad.2018.11.024

43. Gupta AK, Paquet M. Network meta-analysis of the outcome ‚participant complete clearance in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013;169:250-259. doi: 10.1111/bjd.12343

44. Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med. 2019;380:935-946. doi: 10.1056/NEJMoa1811850

45. Bangash HK, Colegio OR. Management of non-melanoma skin cancer in immunocompromised solid organ transplant recipients. Curr Treat Options Oncol. 2012;13:354-376. doi: 10.1007/s11864-012-0195-3

46. Ulrich C, Johannsen A, Röwert-Huber J, et al. Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses. Eur J Dermatol. 2010;20:482-488. doi: 10.1684/ejd.2010.1010

47. Ulrich C, Hackethal M, Ulrich M, et al. Treatment of multiple actinic keratoses with topical diclofenac 3% gel in organ transplant recipients: a series of six cases. Br J Dermatol. 2007;156(suppl 3):40-42. doi: 10.1111/j.1365-2133.2007.07864.x

48. Wu Y, Tang N, Cai L, et al. Relative efficacy of 5-fluorouracil compared with other treatments among patients with actinic keratosis: a network meta-analysis. Dermatol Ther. 2019;32:e12822. doi: 10.1111/dth.12822

49. Stockfleth E, Kerl H, Zwingers T, et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011;165:1101-1108. doi: 10.1111/j.1365-2133.2011.10387.x

50. Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drug Dermatol. 2006;5:156-159.

51. Nichols AJ, Allen AH, Shareef S, et al. Association of human papillomavirus vaccine with the development of keratinocyte carcinomas. JAMA Dermatol. 2017;153:571-574. doi: 10.1001/jamadermatol.2016.5703

52. Nichols AJ, Gonzalez A, Clark ES, et al. Combined systemic and intratumoral administration of human papillomavirus vaccine to treat multiple cutaneous basaloid squamous cell carcinomas. JAMA Dermatol. 2018;154:927-930. doi: 10.1001/jamadermatol.2018.1748

53. Rousseau B, Guillemin A, Duvoux C, et al. Optimal oncologic management and mTOR inhibitor introduction are safe and improve survival in kidney and liver allograft recipients with de novo carcinoma. Int J Cancer. 2019;144:886-896. doi: 10.1002/ijc.31769

54. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004;18:446-449. doi: 10.1111/j.1399-0012.2004.00188.x

55. Euvrard S, Morelon E, Rostaing L, et al; TUMORAPA Study Group. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012;367:329-339. doi: 10.1056/NEJMoa1204166

56. Hoogendijk-van den Akker JM, 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;31:1317-1323. doi: 10.1200/JCO.2012.45.6376

57. Karia PS, Azzi JR, Heher EC, et al. Association of sirolimus use with risk for skin cancer in a mixed-organ cohort of solid-organ transplant recipients with a history of cancer. JAMA Dermatol. 2016;152:533-540. doi: 10.1001/jamadermatol.2015.5548

58. Stratigos A, Garbe C, Lebbe C, et al; European Dermatology Forum (EDF); European Association of Dermato-Oncology (EADO); European Organization for Research and Treatment of Cancer (EORTC). Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer. 2015;51:1989-2007. doi: 10.1016/j.ejca.2015.06.110

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60. Stasko T, Brown MD, Carucci JA, et al; International Transplant-Skin Cancer Collaborative; European Skin Care in Organ Transplant Patients Network. Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Derm Surg. 2004;30:642-650. doi: 10.1111/j.1524-4725.2004.30150.x

61. Telfer NR, Colver GB, Morton CA; British Association of Dermatologists. Guidelines for the management of basal cell carcinoma. Br J Dermatol. 2008;159:35-48. doi: 10.1111/j.1365-2133.2008.08666.x

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

46% expressed a lack of knowledge of the hazards of sun exposure
44% did not recall ever receiving medical advice regarding sun protection
89% did not wear sun-protective clothing
86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

annually—when there is no history of skin cancer
every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
every 1 to 3 months—when there is a history of metastatic disease.

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