Advertisement
Mayo Clinic Proceedings Home

Skin Cancer in Solid Organ Transplant Recipients: A Review for the Nondermatologist

Published:November 02, 2022DOI:https://doi.org/10.1016/j.mayocp.2022.07.004

      Abstract

      Solid organ transplant recipients (SOTRs) are at increased risk for the development of skin cancer compared with the general population, which requires consistent monitoring and management from a multidisciplinary team. The aim of this review is to provide a comprehensive overview for nondermatologist clinicians, outlining skin cancer diagnosis, treatment pearls, and skin cancer prevention strategies as they relate to SOTRs. A comprehensive search of the literature was conducted through the MEDLINE database with search terms including organ transplantation, transplant recipient, skin cancer, cutaneous neoplasms, management, and therapies. The search was limited to the English language and dates ranging from January 1, 2011, to December 28, 2021. All studies were reviewed for inclusion. Skin cancer will develop in more than half of SOTRs at some point in their life, most often nonmelanoma skin cancer such as basal cell carcinoma or squamous cell carcinoma. Melanoma and rarer cutaneous malignant neoplasms, such as Merkel cell carcinoma and Kaposi sarcoma, are also more frequent among SOTRs. A multidisciplinary effort at skin cancer screening and patient education is invaluable to prevent skin cancer–related morbidity and mortality in this population of patients. Reduction in immunosuppressive medications and surgical intervention are effective therapeutic approaches, and more novel systemic therapies including G protein–coupled receptor inhibitors and immune checkpoint inhibitors are possible options when traditional treatment approaches are not feasible. Checkpoint inhibitor therapy, however, comes with the risk of allograft rejection. With a growing and aging SOTR population, it is essential that SOTRs have support from dermatologists and nondermatologists alike in skin cancer prevention and treatment.

      Abbreviations and Acronyms:

      AK (actinic keratosis), BCC (basal cell carcinoma), 5-FU (5-fluorouracil), HHV-8 (human herpesvirus 8), HPV (human papillomavirus), ICI (immune checkpoint inhibitor), KS (Kaposi sarcoma), MCC (Merkel cell carcinoma), MMF (mycophenolate mofetil), mTOR (mechanistic target of rapamycin), NCCN (National Comprehensive Cancer Network), NMSC (nonmelanoma skin cancer), PD-1 (programmed cell death 1), PDT (photodynamic therapy), SCC (squamous cell carcinoma), SOTR (solid organ transplant recipient), UV (ultraviolet)
      Article Highlights
      • Organ transplant recipients have a markedly higher risk for skin cancer compared with the general population.
      • Skin cancer treatments and chemoprevention may necessitate monitoring of multiple organ systems in a multidisciplinary fashion.
      • Strategies to prevent skin cancer development in this population include patient education on photoprotection, regular skin checks, modification of immunosuppression, and treatment of precancerous lesions with appropriate destructive techniques.
      Solid organ transplant recipients (SOTRs) are at increased risk for the development of skin cancer compared with the general population. This increased risk includes many types of cutaneous malignant neoplasms and is highest for cutaneous squamous cell carcinoma (SCC), which some studies estimate to be several hundred times higher than in the general population.
      • Infusino S.D.
      • Loi C.
      • Ravaioli G.M.
      • Piraccini B.M.
      • Bardazzi F.
      • Patrizi A.
      Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience.
      The increase in skin cancer in SOTRs is secondary to the long-term immunosuppressive therapy required for transplanted organ survival, which impairs the immune system’s ability to monitor cells for atypia. Thus, care for the SOTR requires consistent monitoring by a multidisciplinary team including transplant providers, organ-specific specialists, dermatologists, and the primary care physician. Prevention strategies, treatment options, and our overall understanding of skin cancer development in SOTRs are rapidly expanding. Whereas dermatologists ultimately treat and manage many cutaneous malignant neoplasms in these high-risk patients, an understanding of skin cancer risk, development, and management is important across all members of the patient care team. This shared responsibility is especially heightened in communities with limited dermatology access as primary care may assume responsibility for skin cancer prevention and screening. Herein we provide a comprehensive overview for the nondermatologist medical clinician, outlining skin cancer diagnostic and treatment pearls as they relate to SOTRs as well as skin cancer prevention strategies.

      Methods

      A Mayo Clinic Libraries librarian searched the MEDLINE database using the Ovid interface. Search terms included MeSH terms as well as keywords of organ transplantation, transplant recipient, skin cancer, cutaneous neoplasms, management, and therapies. An English-language search filter was employed. A publication date filter limited the results from January 1, 2011, to the day the search was run, December 28, 2021. Article types in our final analysis include all meta-analyses, systematic reviews, randomized controlled trials, guidelines, and prospective and retrospective studies. All articles were evaluated, and articles with robust evidence or those with novel concepts were cited in this review.

      Skin Cancer Types and Treatments

      In both SOTRs and the immunocompetent patient, baseline skin pigmentation, genetic predisposition, age, male sex, and previous exposure to ultraviolet (UV) light play a role in skin cancer development.
      • Chung E.Y.
      • Palmer S.C.
      • Strippoli G.F.
      Interventions to prevent nonmelanoma skin cancers in recipients of a solid organ transplant: systematic review of randomized controlled trials.
      Risk factors unique to organ transplant recipients include age older than 50 years at the time of transplant, pretransplant skin cancer or actinic keratosis history, human papillomavirus (HPV) infection, and thoracic organ transplant.
      • Pinho A.
      • Gouveia M.
      • Cardoso J.C.
      • Xavier M.M.
      • Vieira R.
      • Alves R.
      Non-melanoma skin cancer in Portuguese kidney transplant recipients—incidence and risk factors.
      • Garrett G.L.
      • Blanc P.D.
      • Boscardin J.
      • et al.
      Incidence of and risk factors for skin cancer in organ transplant recipients in the United States.
      • Tufaro A.P.
      • Azoury S.C.
      • Crompton J.G.
      • et al.
      Rising incidence and aggressive nature of cutaneous malignancies after transplantation: an update on epidemiology, risk factors, management and surveillance.
      • Gogia R.
      • Binstock M.
      • Hirose R.
      • Boscardin W.J.
      • Chren M.M.
      • Arron S.T.
      Fitzpatrick skin phototype is an independent predictor of squamous cell carcinoma risk after solid organ transplantation.
      Skin cancer will develop in more than half of SOTRs at some point in their life, most often nonmelanoma skin cancer (NMSC) such as basal cell carcinoma (BCC) or SCC, as transplant patients are estimated to have a 10-fold and 65- to 100-fold increased risk of these malignant neoplasms, respectively.
      • Howard M.D.
      • Su J.C.
      • Chong A.H.
      Skin cancer following solid organ transplantation: a review of risk factors and models of care.
      Melanoma prevalence is also increased in the organ transplant population,
      • Fattouh K.
      • Ducroux E.
      • Decullier E.
      • et al.
      Increasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study.
      as are rare cutaneous malignant neoplasms, such as Merkel cell carcinoma and Kaposi sarcoma. In this population, early recognition of skin cancer and prompt referral to a dermatologist for definitive treatment are paramount to avoid locally advanced and metastatic disease.

      Actinic Keratosis (Precancer)

      Overview

      Actinic keratosis (AK) is a premalignant area of dysplastic keratinocytes manifested as erythematous, scaling macules and patches (Figure A). It is considered a “precancerous” lesion because of its ability to transform into invasive SCC. However, the exact rate at which it becomes malignant or spontaneously regresses is uncertain as estimates for malignant transformation range from less than 1% to 10%.
      • Werner R.N.
      • Sammain A.
      • Erdmann R.
      • Hartmann V.
      • Stockfleth E.
      • Nast A.
      The natural history of actinic keratosis: a systematic review.
      ,
      • Fuchs A.
      • Marmur E.
      The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma.
      Patients with a history of NMSC have higher rates of AK progression into skin cancer.
      • Werner R.N.
      • Sammain A.
      • Erdmann R.
      • Hartmann V.
      • Stockfleth E.
      • Nast A.
      The natural history of actinic keratosis: a systematic review.
      Transplant recipients with systemic immunosuppression often have a higher burden of AKs than the general population does, with a greater likelihood for development of SCC. The risk is estimated to be at least 100-fold that of immunocompetent patients.
      • Poulin Y.
      • Lynde C.W.
      • Barber K.
      • et al.
      Non-melanoma skin cancer in Canada chapter 3: management of actinic keratoses.
      Figure thumbnail gr1
      FigureCutaneous malignant neoplasms and precancers. A, Actinic keratosis. B, Squamous cell carcinoma. C, Basal cell carcinoma. D, Malignant melanoma. E, Merkel cell carcinoma. F, Kaposi sarcoma.

      Treatment

      Procedural therapy for discrete AKs includes techniques such as cryotherapy, curettage, and electrodessication. Field therapy, which is treatment of an entire surface area of a given anatomic location, such as the face, is an important and widely used approach in addressing diffuse AKs, field cancerization, and prevention. Commonly used techniques for field therapy include photodynamic therapy and topical therapies, such as 5-fluorouracil (5-FU), 5-FU with calcipotriene, and imiquimod.

      Squamous Cell Carcinoma

      Overview

      The most common malignant neoplasm seen in SOTRs is cutaneous SCC. Squamous cell carcinoma arises from keratinocytes and typically is manifested as a crusted or scaly, erythematous papule (Figure B).
      • Bruce A.J.
      • Brodland D.G.
      Overview of skin cancer detection and prevention for the primary care physician.
      Organ transplant patients are at risk for worse outcomes, resulting in increased morbidity and a skin cancer–specific mortality that is 9 times higher than in the general population.
      • Howard M.D.
      • Su J.C.
      • Chong A.H.
      Skin cancer following solid organ transplantation: a review of risk factors and models of care.
      ,
      • Manyam B.V.
      • Gastman B.
      • Zhang A.Y.
      • et al.
      Inferior outcomes in immunosuppressed patients with high-risk cutaneous squamous cell carcinoma of the head and neck treated with surgery and radiation therapy.
      ,
      • Bibee K.
      • Swartz A.
      • Sridharan S.
      • et al.
      Cutaneous squamous cell carcinoma in the organ transplant recipient.
      There appears to be an especially increased risk of SCC development among thoracic organ recipients, probably because of the need for higher doses of immunosuppressive medication.
      • Bibee K.
      • Swartz A.
      • Sridharan S.
      • et al.
      Cutaneous squamous cell carcinoma in the organ transplant recipient.
      ,
      • Puza C.J.
      • Beasley G.M.
      • Barbas A.S.
      • Mosca P.J.
      Type of organ transplanted impacts the risk and presentation of cutaneous squamous cell carcinoma in transplant recipients.
      They also have a higher risk of eruptive squamous atypia or keratoacanthomas, which are rapidly growing, crater-shaped tumors that arise from squamous epithelial cells.
      • Blomberg M.
      • He S.Y.
      • Harwood C.
      • et al.
      Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.
      The American Joint Committee on Cancer, 8th edition (AJCC8) and the Brigham and Women's Hospital (BWH) staging systems are most widely used for cutaneous SCC. The BWH staging is based on several risk factors, including tumor size, invasion beyond subcutaneous fat, large-caliber perineural invasion, and poor histologic differentiation. In the AJCC8 classification system, risk factors are tumor size and presence of bone invasion or perineural or deep invasion. Neither staging system incorporates immunosuppression as a high-risk feature. The National Comprehensive Cancer Network (NCCN) categorizes SCCs into low risk, high risk, and very high risk on the basis of recurrence status, size, histologic features, and patient features (including immunosuppression). Per the NCCN, all immunosuppressed patients fall within at least the high-risk category as risk categorization is based on the highest risk factor present (Table 1).
      Table 1Cutaneous Squamous Cell Carcinoma “High-Risk” Features
      AJCC high-risk featuresNCCN high-risk featuresBWH high-risk features
      Anatomic location of primary tumorTumor located on ear or hair-bearing lipTumor larger than 10 mm on the forehead, scalp, cheek, and neck or tumor larger than 6 mm on the ears, eyelids, nose, temple, lips, and periauricular or periorbital area
      Site of chronic inflammation or prior radiation treatment
      Histologic/clinical featuresPoorly differentiated or undifferentiatedModerately or poorly differentiatedPoorly differentiated
      Poorly defined borders
      Depth/tumor growthPerineural invasionRapidly growing tumorPerineural invasion ≥0.1 mm
      Tumor depth >2 mmTumor invasion beyond fat
      Clark level >IVTumor diameter ≥2 cm
      Other featuresRecurrent tumor
      Immunosuppression treatment
      Neurologic symptoms
      AJCC, American Joint Committee on Cancer; BWH, Brigham and Women’s Hospital; NCCN, National Comprehensive Cancer Network.
      Studies have found that high-risk tumors are associated with increased risk of nodal metastases.
      • Karia P.S.
      • Jambusaria-Pahlajani A.
      • Harrington D.P.
      • Murphy G.F.
      • Qureshi A.A.
      • Schmults C.D.
      Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital Tumor Staging for cutaneous squamous cell carcinoma.
      Poor outcomes, defined by local recurrence, nodal metastases, and disease-specific death, are frequent among SOTRs with advanced tumor stage as defined by either AJCC8 or BWH staging.
      • Blechman A.B.
      • Carucci J.A.
      • Stevenson M.L.
      Stratification of poor outcomes for cutaneous squamous cell carcinoma in immunosuppressed patients using the American Joint Committee on Cancer Eighth Edition and Brigham and Women’s Hospital staging systems.

      Treatment

      Reduction of immunosuppressive medications has been reported to be an effective therapeutic strategy for transplant-associated skin cancer.
      • Otley C.C.
      • Berg D.
      • Ulrich C.
      • et al.
      Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey.
      However, decreasing immunosuppression can also increase the risk of transplanted organ rejection, so the risks and potential benefits of this approach must be considered in partnership with transplant specialists and close monitoring.
      For high-risk tumors, both Mohs surgery and wide local excision can be considered. For tumors of very high risk, it is recommended that patients undergo Mohs micrographic surgery or complete circumferential peripheral and deep margin assessment for the highest likelihood of local tumor control. With Mohs surgery or complete circumferential peripheral and deep margin assessment, 100% of the margin is assessed by en face processing compared with approximately 1% of the margin assessed with standard (bread-loafed) processing with a wide local excision. The advantages of Mohs surgery are the complete histologic evaluation of margins, the ability to confirm clear margins at the time of surgery before tissue rearrangement for reconstruction, and the ability for tissue sparing in critical anatomic locations.
      In patients with locally advanced or metastatic cutaneous SCC, a multidisciplinary discussion involving dermatology, head and neck surgery, and surgical oncology specialists helps determine the most appropriate resection strategy. The radiation oncologist will guide the plan and administration of adjuvant or palliative radiation. Input from a medical oncologist is essential for managing systemic treatments. Epidermal growth factor receptor inhibitors, such as cetuximab and panitumumab, are a systemic option for widely metastatic disease. Common adverse effects include papulopustular eruptions and paronychia. Immune checkpoint inhibitors (ICIs), such as cemiplimab, target programmed cell death 1 (PD-1) and have been approved for nonsurgical candidates with locally advanced SCC or metastatic SCC. Currently, data regarding the efficacy and safety of ICIs among SOTRs are limited to case series and reports. For example, use of ICIs in transplant recipients with locally advanced or metastatic SCC has demonstrated improved overall and disease-specific survival in several small retrospective reviews.
      • Abdel-Wahab N.
      • Safa H.
      • Abudayyeh A.
      • et al.
      Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature.
      ,
      • Murakami N.
      • Mulvaney P.
      • Danesh M.
      • et al.
      A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.
      The use of ICIs in SOTRs carries a substantial risk of transplanted organ rejection, which can be life-threatening in this population,
      • Abdel-Wahab N.
      • Safa H.
      • Abudayyeh A.
      • et al.
      Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature.
      and thus further research on optimization of these medications is necessary.
      For eruptive keratoacanthomas, Food and Drug Administration–approved treatments in SOTRs are lacking. Off-label treatments include intralesional 5-FU, intralesional methotrexate, intralesional bleomycin, and systemic retinoids such as acitretin. The safety of intralesional therapies has not been studied in transplant patients in large retrospective cohort studies.
      • Blomberg M.
      • He S.Y.
      • Harwood C.
      • et al.
      Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.
      Surgical interventions, such as wide local excision, Mohs micrographic surgery, or electrodessication and curettage, are frequently employed.

      Basal Cell Carcinoma

      Overview

      Basal cell carcinoma is the most common type of skin cancer among immunocompetent patients, although its incidence is lower than that of SCC in immunosuppressed patients.
      • Infusino S.D.
      • Loi C.
      • Ravaioli G.M.
      • Piraccini B.M.
      • Bardazzi F.
      • Patrizi A.
      Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience.
      There are several different subtypes of BCC; most occur on sun-exposed areas. Subtypes commonly seen include superficial, nodular, micronodular, infiltrative, morpheaform, and pigmented. Early BCCs are classically manifested as pearly, pink papules with a rolled border and telangiectasia, whereas advanced tumors can be large plaques or nodules with central ulceration and a raised, indurated border (Figure C).
      • Bruce A.J.
      • Brodland D.G.
      Overview of skin cancer detection and prevention for the primary care physician.

      Treatment

      Treatment of BCC in SOTRs is approached as in immunocompetent patients. Unlike SCCs, BCCs have a much more limited biologic potential for metastasis and death, with treatment emphasis instead focused on limiting morbidity from disease. The most common treatment approaches are superficial destructive modalities and surgical techniques including curettage, cryosurgery, wide local excision, and Mohs micrographic surgery. Systemic agents are also available for locally advanced and metastatic BCC.
      • Kim J.Y.
      • Kozlow J.H.
      • Mittal B.
      • et al.
      Guidelines of care for the management of basal cell carcinoma.
      Systemic therapies include vismodegib and sonidegib, which are smoothened inhibitors. Smoothened is a G protein–coupled receptor in the hedgehog pathway whose overactivity is implicated in the formation of BCC. These agents have not been well studied in SOTRs, with evidence currently limited to case reports.
      • Rahatli S.
      • Oguz A.
      • Altundag O.
      • Haberal M.
      Vismodegib experience in a renal transplant patient with basal cell carcinoma.
      Vismodegib has been used successfully to treat advanced BCC in a heart transplant patient concurrently receiving cyclosporine in addition to multiple renal transplant patients.
      • Rahatli S.
      • Oguz A.
      • Altundag O.
      • Haberal M.
      Vismodegib experience in a renal transplant patient with basal cell carcinoma.
      • Cusack C.A.
      • Nijhawan R.
      • Miller B.
      • et al.
      Vismodegib for locally advanced basal cell carcinoma in a heart transplant patient.
      • Koelblinger P.
      • Dummer R.
      • Laimer M.
      • et al.
      Vismodegib for recurrent locally destructive basal cell carcinoma in a renal transplant patient.
      As for SCC, the ICI cemiplimab has been approved as the first immunotherapeutic regimen for locally advanced BCC. According to a phase 2 trial conducted by Stratigos et al,
      • Stratigos A.J.
      • Sekulic A.
      • Peris K.
      • et al.
      Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.
      cemiplimab was reported to have a clinically significant benefit among patients who were previously treated with hedgehog inhibitors but are no longer candidates for this medication. Investigations examining its safety and efficacy among SOTRs are limited, and therefore its use in this population is cautioned.
      • Damsin T.
      • Lebas E.
      • Marchal N.
      • Rorive A.
      • Nikkels A.F.
      Cemiplimab for locally advanced and metastatic basal cell carcinoma.

      Melanoma

      Overview

      Melanomas are malignant neoplasms of melanocytes, with significant potential for morbidity and mortality among immunocompetent and immunosuppressed patients. They can have a variety of presentations, including pigment variations within the same lesion and irregularities of shape or size. Melanoma may appear as a dark papule in the nodular form, a multipigmented patch or plaque in the superficial spreading form, an irregularly pigmented patch in the lentigo maligna form, or spreading lesions in the palms or soles in the acral lentiginous form (Figure D).
      • Bruce A.J.
      • Brodland D.G.
      Overview of skin cancer detection and prevention for the primary care physician.
      Organ transplant recipients have an increased risk of melanoma in comparison to the general population, estimated to be approximately 2.5 to 5 times higher for SOTRs in general, with a particularly increased risk in Black patients.
      • Howard M.D.
      • Su J.C.
      • Chong A.H.
      Skin cancer following solid organ transplantation: a review of risk factors and models of care.
      Organ transplant recipients with melanoma in situ or thin melanomas (<1 mm Breslow thickness) have survival and recurrence rates similar to those of immunocompetent patients.
      • Fattouh K.
      • Ducroux E.
      • Decullier E.
      • et al.
      Increasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study.
      However, transplant patients are more likely to present with advanced melanoma and to have an increased rate of death compared with matched controls.
      • Vajdic C.M.
      • Chong A.H.
      • Kelly P.J.
      • et al.
      Survival after cutaneous melanoma in kidney transplant recipients: a population-based matched cohort study.
      These findings suggest that melanoma has a more aggressive disease course among transplant recipients.
      • Vajdic C.M.
      • Chong A.H.
      • Kelly P.J.
      • et al.
      Survival after cutaneous melanoma in kidney transplant recipients: a population-based matched cohort study.
      Staging of melanoma is primarily dependent on Breslow depth and secondarily on presence of ulceration. Breslow depth is a histologic measurement from the granular layer to the deepest invasive portion. Gene expression profiling is a newer tool designed to help with prognostication of melanoma. It has potential to expand our current staging system, but it is not yet the mainstay of treatment and requires further study and validation.
      • Chan W.H.
      • Tsao H.
      Consensus, controversy, and conversations about gene expression profiling in melanoma.

      Treatment

      Melanomas are most often treated with wide local excision with margins determined by the Breslow depth. In anatomically constrained areas, Mohs micrographic surgery may be used in combination with immunostains. Multiple studies reported improved rates of disease-free survival and overall survival in the Mohs surgery cohort compared with wide local excision.
      • Hanson J.
      • Demer A.
      • Liszewski W.
      • Foman N.
      • Maher I.
      Improved overall survival of melanoma of the head and neck treated with Mohs micrographic surgery versus wide local excision.
      Management of melanoma in SOTRs is similar to that in immunocompetent patients of similar stage, with Breslow depth determining margins for surgical excision and need for sentinel lymph node biopsy.
      • Zwald F.O.
      • Christenson L.J.
      • Billingsley E.M.
      • et al.
      Melanoma in solid organ transplant recipients.
      For stage T1b tumors and above (Breslow depth of 0.8 to 1.0 mm with or without ulceration or <0.8 mm with ulceration), sentinel lymph node biopsy is recommended. Lymph node biopsy results have an impact on staging, prognostication, and treatment. Metastatic melanomas that have BRAF mutations can be treated with BRAF inhibitors such as dabrafenib.
      • Mittal A.
      • Colegio O.R.
      Skin cancers in organ transplant recipients.
      Immunotherapy for melanoma has a substantial risk of transplant rejection in SOTRs; however, the use of checkpoint inhibitors is becoming more prevalent in SOTRs as a final option in patients who have failed to respond to all other possible therapies. Ipilimumab, a cytotoxic lymphocyte antigen 4 inhibitor approved for the treatment of melanoma in immunocompetent patients, has several reports of safe administration in liver and kidney transplant recipients, whereas PD-1 inhibitors have been associated with a relatively higher risk of acute rejection.
      • Nguyen L.S.
      • Ortuno S.
      • Lebrun-Vignes B.
      • et al.
      Transplant rejections associated with immune checkpoint inhibitors: a pharmacovigilance study and systematic literature review.
      ,
      • Kumar V.
      • Shinagare A.B.
      • Rennke H.G.
      • et al.
      The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature.
      Although minimizing transplant immunosuppression is a well-studied therapeutic approach for NMSC, its efficacy for melanoma has not been as comprehensively investigated.
      • Fattouh K.
      • Ducroux E.
      • Decullier E.
      • et al.
      Increasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study.
      ,
      • Otley C.C.
      • Berg D.
      • Ulrich C.
      • et al.
      Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey.

      Merkel Cell Carcinoma

      Overview

      Merkel cell carcinoma (MCC) is an aggressive primary cutaneous neuroendocrine carcinoma with a predilection for the head and neck region of White patients older than 50 years and has a significant risk of metastasis. It typically is manifested as a rapidly growing red to purple, dome-shaped, smooth nodule and is often asymptomatic (Figure E). There is a positive association of MCC with UV radiation exposure and immunosuppression. Immunocompromised patients with T-cell dysfunction have a markedly increased incidence of this disease as MCC is 5 to 10 times more likely to develop in SOTRs.
      • Becker J.C.
      Merkel cell carcinoma.
      Merkel cell polyomavirus is a human polyomavirus that was discovered in 2008, and its oncogenic role in the pathogenesis of 80% of MCCs has been reported in several studies.
      • Feng H.
      • Shuda M.
      • Chang Y.
      • Moore P.S.
      Clonal integration of a polyomavirus in human Merkel cell carcinoma.

      Treatment

      Current treatment guidelines from the NCCN recommend management of the primary tumor with wide local excision with 1- to 2-cm margins, with or without adjuvant radiation therapy. Notably, a sentinel lymph node biopsy is recommended for clinically node-negative tumors. Immunotherapy is an alternative approach based on the identification of several novel therapeutic targets identified in the Merkel cell polyomavirus–specific cellular immune response.
      • Zanetti I.
      • Coati I.
      • Alaibac M.
      Interaction between Merkel cell carcinoma and the immune system: pathogenetic and therapeutic implications.
      Avelumab and pembrolizumab are Food and Drug Administration approved for treatment of recurrent locally advanced or metastatic MCC; however, the significant risk of transplanted organ rejection and loss associated with checkpoint inhibitors in SOTRs must be considered.
      • Bradford D.
      • Demko S.
      • Jin S.
      • et al.
      FDA accelerated approval of pembrolizumab for recurrent locally advanced or metastatic Merkel cell carcinoma.
      ,
      • Maggiore U.
      • Pascual J.
      The bad and the good news on cancer immunotherapy: implications for organ transplant recipients.

      Kaposi Sarcoma

      Overview

      Kaposi sarcoma (KS) is a malignant vascular tumor associated with reactivation of latent human herpesvirus 8 (HHV-8) due to immunosuppression and, less commonly, through donor-derived infection. It is clinically manifested as erythematous to violaceous macules, patches, plaques, papules, or nodules on the skin, mucous membranes, lymph nodes, or other organs (Figure F). Because of its relationship to immunosuppression, there is a 200-fold increased risk of KS development in transplant recipients.
      • Delyon J.
      • Rabate C.
      • Euvrard S.
      • et al.
      Management of Kaposi sarcoma after solid organ transplantation: a European retrospective study.
      Rates of KS development after transplant vary by geographic region. For example, among renal transplant recipients, KS development is less common in northern and western parts of the world (approximately 0.5% of SOTRs) and higher in Mediterranean countries and some parts of the Middle East (approximately 5% of SOTRs).
      • Hosseini-Moghaddam S.M.
      • Soleimanirahbar A.
      • Mazzulli T.
      • Rotstein C.
      • Husain S.
      Post renal transplantation Kaposi’s sarcoma: a review of its epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy.
      This is reflective of HHV-8 being endemic to certain regions of the world.

      Treatment

      A multicenter retrospective study examining treatment of SOTRs diagnosed with KS found that more than 80% of the patients examined had a good treatment response. This suggests that KS after organ transplant is a manageable disease. Of these patients, 95% were treated by reducing organ transplant immunosuppression medications, either as the sole treatment or in conjunction with conversion to mechanistic target of rapamycin (mTOR) inhibitors or use of chemotherapy agents.
      • Delyon J.
      • Rabate C.
      • Euvrard S.
      • et al.
      Management of Kaposi sarcoma after solid organ transplantation: a European retrospective study.
      As such, reducing immunosuppression is the cornerstone of posttransplant KS therapeutic management. Systemic chemotherapy includes pegylated liposomal doxorubicin or other cytotoxic agents, such as vinblastine, bleomycin, taxane, etoposide, and gemcitabine. The role of antiviral therapy against HHV-8 is limited.
      • Delyon J.
      • Rabate C.
      • Euvrard S.
      • et al.
      Management of Kaposi sarcoma after solid organ transplantation: a European retrospective study.
      ,
      • Casper C.
      New approaches to the treatment of human herpesvirus 8–associated disease.

      Interventions for Skin Cancer Prevention

      Prevention is the cornerstone of skin health in transplant recipients. Prevention strategies require active involvement of the patient and the patient’s medical team. This includes education, practicing photoprotective measures, pharmaceutical and procedural interventions to prevent skin cancer, and regular skin cancer screenings. A dermatology referral is often made at the time of organ transplant; however, the critical role of early skin cancer prevention and education is often deferred to primary care. Detailed education should begin before potential organ transplant as UV light exposure is accumulated during a lifetime.

      Pretransplant Screening

      Transplant teams should perform a risk assessment for all SOTRs to determine the likelihood for development of skin cancers during the initial evaluation. Any preexisting skin cancer or precancers should be promptly treated before transplant. Skin cancers during the pretransplant period have bearing on posttransplant risk and screening recommendations.

      Posttransplant Screening

      The frequency of posttransplant skin evaluations varies by patient risk factors. A 2019 expert panel established guidelines for initial skin cancer screening in SOTRs without a previous history of skin cancer.
      • Crow L.D.
      • Jambusaria-Pahlajani A.
      • Chung C.L.
      • et al.
      Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.
      High-risk patients included heart or lung transplant recipients, patients older than 50 years at time of transplant, and male patients. High-risk White patients should begin regular screenings within 2 years after transplant, and all Hispanic, Asian, and high-risk Black or African descent patients should begin screening within 5 years after transplant. There was no consensus in low-risk Black SOTRs. Patients with a prior history of skin cancer should continue skin cancer screenings as directed by their dermatologist.
      • Crow L.D.
      • Jambusaria-Pahlajani A.
      • Chung C.L.
      • et al.
      Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.
      Most posttransplant clinical practice guidelines recommend at least annual skin cancer screening for the remainder of life; more frequent screening by a dermatologist may be necessary in high-risk patients. Some guidelines suggest that screening can be performed by primary care providers for low-risk patients.
      • Acuna S.A.
      • Huang J.W.
      • Scott A.L.
      • et al.
      Cancer screening recommendations for solid organ transplant recipients: a systematic review of clinical practice guidelines.
      The primary care physician plays an important role in performing initial skin checks and ensuring that patients are evaluated by a dermatologist within the appropriate time frame. A population study of 10,183 SOTRs in Canada reported poor adherence to regular dermatology visits, with only 2.1% adhering to annual dermatology visits during the 18-year evaluation period.
      • Chan A.W.
      • Fung K.
      • Austin P.C.
      • et al.
      Improved keratinocyte carcinoma outcomes with annual dermatology assessment after solid organ transplantation: population-based cohort study.
      Primary care providers are uniquely positioned to encourage appropriate skin cancer evaluations to prevent skin cancer–related morbidity and mortality in this population.
      Posttransplant skin cancer screenings should include a full-body skin examination, including evaluation of oral mucosa and genitalia. Non-White SOTRs have been reported to have a higher incidence of cutaneous malignant disease involving the genitalia, including genital SCC associated with high-risk HPV subtypes.
      • Nadhan K.S.
      • Larijani M.
      • Abbott J.
      • Doyle A.M.
      • Linfante A.W.
      • Chung C.L.
      Prevalence and types of genital lesions in organ transplant recipients.

      Patient Education

      Counseling and education of SOTRs about modifiable risk factors and skin cancer detection strategies are critical (Table 2). All clinicians involved in care of SOTRs can have an impact on encouraging skin cancer prevention. SOTRs who are advised to use sunscreen by any health care professional are significantly more likely to practice these photoprotective measures than those who are not.
      • Mihalis E.L.
      • Wysong A.
      • Boscardin W.J.
      • Tang J.Y.
      • Chren M.M.
      • Arron S.T.
      Factors affecting sunscreen use and sun avoidance in a U.S. national sample of organ transplant recipients.
      However, a 2020 systematic review found that educational intervention for limiting sun exposure in transplant recipients improved sun safety measures but did not lead to ultimate reduction in skin cancer.
      • James L.J.
      • Saglimbene V.
      • Wong G.
      • et al.
      Behavioural and pharmaceutical interventions for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomised controlled trials.
      Further investigation on this topic is warranted to identify the most effective means of educational intervention.
      • James L.J.
      • Saglimbene V.
      • Wong G.
      • et al.
      Behavioural and pharmaceutical interventions for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomised controlled trials.
      ,
      • Wu S.Z.
      • Jiang P.
      • DeCaro J.E.
      • Bordeaux J.S.
      A qualitative systematic review of the efficacy of sun protection education in organ transplant recipients.
      Table 2Skin Cancer Education and Counseling Highlights for SOTR
      • Sun protection with high SPF sunscreen (even if it is cloudy)
      • Use of physical UV light barriers, such as photoprotective clothing, hats, sunglasses
      • Avoidance of exposure to UV light by limiting outdoor activity during peak daylight (10 am to 4 pm)
      • Abstinence from tanning or artificial UV sources
      • Education on the ABCDE rule for skin cancer identification: asymmetry, border, color, diameter, elevation/evolving
      • Monthly self-examination of skin and annual skin examination by a dermatologist or primary care physician experienced with skin cancer
      SOTR, solid organ transplant recipient; SPF, sun protection factor; UV, ultraviolet.

      Posttransplant Pharmaceutical Modifications

      After organ transplant, patients must begin immunosuppressive medication to prevent transplanted organ rejection. Patients often begin with induction therapy at the time of transplant and then transition to lifelong immunosuppressive maintenance therapy. Additional antimicrobial prophylaxis is frequently necessary, given the increased risk for infection with immunosuppression.
      Maintenance immunosuppression therapy often includes the combination of calcineurin inhibitors and mycophenolate mofetil (MMF). Older immunosuppressive agents, such as azathioprine and cyclosporine, have been associated with higher risk of posttransplant cancer, including cutaneous SCC.
      • Infusino S.D.
      • Loi C.
      • Ravaioli G.M.
      • Piraccini B.M.
      • Bardazzi F.
      • Patrizi A.
      Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience.
      ,
      • Blomberg M.
      • He S.Y.
      • Harwood C.
      • et al.
      Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.
      ,
      • Jiyad Z.
      • Olsen C.M.
      • Burke M.T.
      • Isbel N.M.
      • Green A.C.
      Azathioprine and risk of skin cancer in organ transplant recipients: systematic review and meta-analysis.
      Current evidence investigating the effect of various induction immunosuppression therapies on the risk of skin cancer is inconclusive.
      • Blomberg M.
      • He S.Y.
      • Harwood C.
      • et al.
      Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.

      Modification of Immunosuppression

      It is well established that increased duration and potency of immunosuppressive regimens are associated with an increased incidence of skin cancer in SOTRs.
      • Londoño M.C.
      • Rimola A.
      • O’Grady J.
      • Sanchez-Fueyo A.
      Immunosuppression minimization vs. complete drug withdrawal in liver transplantation.
      Several studies have suggested that conversion from calcineurin inhibitors to mTOR inhibitors, including sirolimus and everolimus, reduces incidence of posttransplant NMSC.
      • Howard M.D.
      • Su J.C.
      • Chong A.H.
      Skin cancer following solid organ transplantation: a review of risk factors and models of care.
      ,
      • Murray S.L.
      • Daly F.E.
      • O’Kelly P.
      • et al.
      The impact of switching to mTOR inhibitor–based immunosuppression on long-term non-melanoma skin cancer incidence and renal function in kidney and liver transplant recipients.
      • Alberú J.
      • Pascoe M.D.
      • Campistol J.M.
      • et al.
      Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor–free immunotherapy: 24-month results from the CONVERT trial.
      • Dantal J.
      • Morelon E.
      • Rostaing L.
      • et al.
      Sirolimus for secondary prevention of skin cancer in kidney transplant recipients: 5-year results.
      • Funk-Debleds P.
      • Ducroux E.
      • Guillaud O.
      • et al.
      Subsequent nonmelanoma skin cancers and impact of immunosuppression in liver transplant recipients.
      • Karia P.S.
      • Azzi J.R.
      • Heher E.C.
      • Hills V.M.
      • Schmults C.D.
      Association of sirolimus use with risk for skin cancer in a mixed-organ cohort of solid-organ transplant recipients with a history of cancer.
      • Yanik E.L.
      • Siddiqui K.
      • Engels E.A.
      Sirolimus effects on cancer incidence after kidney transplantation: a meta-analysis.
      • Knoll G.A.
      • Kokolo M.B.
      • Mallick R.
      • et al.
      Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.
      • Euvrard S.
      • Morelon E.
      • Rostaing L.
      • et al.
      Sirolimus and secondary skin-cancer prevention in kidney transplantation.
      • Gu Y.H.
      • Du J.X.
      • Ma M.L.
      Sirolimus and non-melanoma skin cancer prevention after kidney transplantation: a meta-analysis.
      • Phan K.
      • Moloney F.J.
      • Hogarty D.T.
      • Lenane P.
      • McColl D.
      • Yazdabadi A.
      Mammalian target of rapamycin (mTOR) inhibitors and skin cancer risk in nonrenal solid organ transplant recipients: systematic review and meta-analysis.
      One systematic review evaluating preventive measures for skin cancer development in SOTRs found that conversion to an mTOR inhibitor from other immunosuppressants was the only intervention to effectively prevent skin cancer.
      • Chung E.Y.
      • Palmer S.C.
      • Strippoli G.F.
      Interventions to prevent nonmelanoma skin cancers in recipients of a solid organ transplant: systematic review of randomized controlled trials.
      However, there is evidence of higher overall mortality and medication adverse events with the use of mTOR inhibitor therapy.
      • James L.J.
      • Saglimbene V.
      • Wong G.
      • et al.
      Behavioural and pharmaceutical interventions for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomised controlled trials.
      ,
      • Badve S.V.
      • Pascoe E.M.
      • Burke M.
      • et al.
      Mammalian target of rapamycin inhibitors and clinical outcomes in adult kidney transplant recipients.
      • Alter M.
      • Satzger I.
      • Schrem H.
      • Kaltenborn A.
      • Kapp A.
      • Gutzmer R.
      Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR-inhibitors in organ transplant recipients.
      • Hoogendijk-van den Akker J.M.
      • Harden P.N.
      • Hoitsma A.J.
      • et al.
      Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus.
      • Campbell S.B.
      • Walker R.
      • Tai S.S.
      • Jiang Q.
      • Russ G.R.
      Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer.
      Therefore, the risk-benefit balance has to be considered with mTOR therapy.
      There are also data that transitioning to MMF monotherapy decreases risk of posttransplant NMSC,
      • Aguiar D.
      • Martínez-Urbistondo D.
      • Baroja-Mazo A.
      • et al.
      Real-world multicenter experience of immunosuppression minimization among 661 liver transplant recipients.
      and some studies have supported a similar finding with mycophenolic acid, the active form of MMF.
      • Coghill A.E.
      • Johnson L.G.
      • Berg D.
      • Resler A.J.
      • Leca N.
      • Madeleine M.M.
      Immunosuppressive medications and squamous cell skin carcinoma: nested case-control study within the skin cancer after organ transplant (SCOT) cohort.
      Based on these studies, early optimization of immunosuppressive regimens with transition to mTOR inhibitors or MMF may help decrease the risk of posttransplant skin cancers.

      Modification of Antimicrobial Prophylaxis

      The antifungal medication voriconazole, which is often used for fungal prophylaxis, particularly after lung transplant, has been associated with as much as a 73% increased risk for development of cutaneous SCC. This is believed to be secondary to photosensitizing properties of this medication. Posaconazole appears to have a better safety profile, especially in patients at high risk of skin cancer development.
      • Howard M.D.
      • Su J.C.
      • Chong A.H.
      Skin cancer following solid organ transplantation: a review of risk factors and models of care.
      ,
      • Feist A.
      • Lee R.
      • Osborne S.
      • Lane J.
      • Yung G.
      Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole.

      Pharmaceutical Skin Cancer Prevention

      Whereas regular screening and photoprotective measures are critical in SOTRs, additional medical interventions can be used to actively reduce the risk of skin cancer development. Actinic keratoses are precursors to SCCs. Therefore, proactive treatment of these precancerous lesions can greatly reduce risk of SCC development. For patients with many AKs or evidence of extensive damage from sun-exposed skin, individual destruction of lesions can be extremely burdensome, and patients often need to return for repeated treatments. In these patients, field treatment can be extremely useful and efficient in preventing skin cancer development.

      Topical Therapy

      Topical 5-FU, imiquimod, and diclofenac have been found to be safe and effective field treatments of SOTRs. Fluorouracil 5% cream inhibits thymidylate synthetase, an enzyme implicated in DNA synthesis, and topical application results in lesional inflammation and superficial erosion. Topical imiquimod 5% cream modifies immune response with direct action by binding to Toll-like receptors 7 and 8 on macrophages, monocytes, and dendritic cells and indirectly by release of local cytokines. Application produces local inflammation, and patients may report influenza-like symptoms. Topical diclofenac sodium 3% gel in hyaluronic acid is a nonsteroidal anti-inflammatory drug that inhibits inducible cyclooxygenase 2 and reduces prostaglandin synthesis. The mechanism of action of topical diclofenac in the treatment of AKs is not fully understood. A 2019 systematic review of field-directed regimens in SOTRs (including 5-FU, imiquimod, and diclofenac) found complete clearance rates of 27.5% to 62.1% for imiquimod, 41% for diclofenac, and 11% for 5-FU.
      • Heppt M.V.
      • Steeb T.
      • Niesert A.C.
      • et al.
      Local interventions for actinic keratosis in organ transplant recipients: a systematic review.
      Topical treatments can be made more effective by wrapping the area with dressings under occlusion after medication application. These “chemowraps” provide more effective clearance of AKs and can be used to better delineate surgical margins of invasive carcinoma.
      • Mann M.
      • Berk D.R.
      • Petersen J.
      Chemowraps as an adjuvant to surgery for patients with diffuse squamous cell carcinoma of the extremities.
      The combination of 5-FU and calcipotriene offers the advantage of a shorter treatment course compared with 5-FU alone. Tirbanibulin 1% ointment is a newer agent approved for topical treatment of AKs with a relatively short 5-day treatment course. Tirbanibulin works as an inhibitor of microtubules and SRC kinase signaling.
      • Blauvelt A.
      • Kempers S.
      • Lain E.
      • et al.
      Phase 3 trials of tirbanibulin ointment for actinic keratosis.
      There are currently no studies examining use of these agents specifically in SOTRs.

      Photodynamic Therapy

      Photodynamic therapy (PDT) combines light energy with topical photosensitizers that generate cytotoxic reactive oxygen species and have a tumoricidal effect on abnormal cells. Photodynamic therapy has had clearance of AKs at a rate of 40% to 76.4%.
      • Heppt M.V.
      • Steeb T.
      • Niesert A.C.
      • et al.
      Local interventions for actinic keratosis in organ transplant recipients: a systematic review.
      Topical photosensitizers commonly used in PDT include 5-aminolevulinic acid and methyl aminolevulinate.
      • Braathen L.R.
      • Szeimies R.M.
      • Basset-Seguin N.
      • et al.
      Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus.
      A 2019 meta-analysis examined the role of PDT in the prevention and treatment of AKs and SCC in SOTRs and found favorable response rates.
      • Liew Y.C.
      • de Souza N.N.
      • Sultana R.G.
      • Oh C.C.
      Photodynamic therapy for the prevention and treatment of actinic keratosis/squamous cell carcinoma in solid organ transplant recipients: a systematic review and meta-analysis.
      There appears to be a similar response to PDT in SOTRs and immunocompetent patients; however, SOTRs have higher rates of recurrence after treatment.
      • Morton C.A.
      A synthesis of the world’s guidelines on photodynamic therapy for non-melanoma skin cancer.
      Daylight PDT offers a convenient and effective skin cancer prevention strategy, allowing patients to use natural sunlight to activate topical photosensitizers. A 2020 randomized, intrasubject controlled trial using a split-face design to directly compare daylight PDT with cryotherapeutic destruction of lesions found a reduction in new lesions with daylight PDT and reported a patient preference for the PDT treatment over cryotherapy.
      • Bernad I.
      • Aguado L.
      • Núñez-Córdoba J.M.
      • Redondo P.
      Daylight photodynamic therapy for prevention of new actinic keratosis and keratinocyte carcinomas in organ transplants. A cryotherapy-controlled randomized clinical trial.
      Another trial found improved clearance rates in pretreating areas with ablative fractional laser before performing daylight PDT with a median complete response of 74% across all AK grades in combined treatment vs 46% in daylight PDT alone after 3 months.
      • Togsverd-Bo K.
      • Lei U.
      • Erlendsson A.M.
      • et al.
      Combination of ablative fractional laser and daylight-mediated photodynamic therapy for actinic keratosis in organ transplant recipients—a randomized controlled trial.
      Overall, PDT offers an effective option for skin cancer prevention; however, before initiation of this treatment, patients should be advised of the expected reaction to treatment, which can be uncomfortable: inflammation, skin redness and peeling, discomfort (burning and stinging), and crusting or blistering of lesions.
      • Bernad I.
      • Aguado L.
      • Núñez-Córdoba J.M.
      • Redondo P.
      Daylight photodynamic therapy for prevention of new actinic keratosis and keratinocyte carcinomas in organ transplants. A cryotherapy-controlled randomized clinical trial.

      Systemic Chemoprevention

      Systemic chemoprevention with agents such as oral acitretin, nicotinamide, and capecitabine (a 5-FU prodrug) is another method to decrease the risk of posttransplant NMSC. A 2020 meta-analysis limited to placebo-controlled, randomized controlled trials evaluated the efficacy of acitretin and nicotinamide in the prevention of BCC, SCC, and AK in SOTRs and found a significant risk reduction. No significant difference was found between acitretin and nicotinamide.
      • Tee L.Y.
      • Sultana R.
      • Tam S.Y.
      • Oh C.C.
      Chemoprevention of keratinocyte carcinoma and actinic keratosis in solid-organ transplant recipients: systematic review and meta-analyses.
      Oral acitretin is generally started at a low dose of 10 mg daily and up-titrated as tolerated, not exceeding 30 mg daily.
      • Herold M.
      • Good A.J.
      • Nielson C.B.
      • Longo M.I.
      Use of topical and systemic retinoids in solid organ transplant recipients.
      Its cancer-protective effects appear to be limited to when the patient is receiving the medication. It has several adverse effects, including teratogenicity, mucocutaneous xerosis, hair loss, liver toxic effects, lipid abnormalities, and myalgia or arthralgia, that may limit its use.
      Nicotinamide is generally well tolerated. A dose of 500 mg twice daily has been found to have protective effects against UV radiation and enhancement of DNA repair, reducing the incidence of AK and NMSC. A study assessing the efficacy of nicotinamide 500 mg daily in a small cohort of SOTRs reported significant reduction in AK size in 88% of patients and complete clinical regression in 42%. Within the control group, 91% had an increase in AK size or new AKs, and 7 preexisting AKs (among 19 patients) progressed to SCC.
      • Drago F.
      • Ciccarese G.
      • Cogorno L.
      • Calvi C.
      • Marsano L.A.
      • Parodi A.
      Prevention of non-melanoma skin cancers with nicotinamide in transplant recipients: a case-control study.
      Adverse effects of nicotinamide include allergic reaction, gastrointestinal intolerance, muscle pain, and liver toxic effects at high doses. As with oral retinoid therapy, the chemopreventive effects of nicotinamide are not maintained after cessation. Both nicotinamide and acitretin require continuous administration for chemoprevention and avoidance of rebound NMSC.
      Oral capecitabine is a prodrug that is converted to its active form 5-FU in the liver. A systematic review of capecitabine use in SOTRs found low-dose oral capecitabine to be associated with at least a 50% reduction in SCCs during the first 12 months of treatment in addition to a reduction in AKs.
      • Schauder D.M.
      • Kim J.
      • Nijhawan R.I.
      Evaluation of the use of capecitabine for the treatment and prevention of actinic keratoses, squamous cell carcinoma, and basal cell carcinoma: a systematic review.
      Adverse effects included fatigue, nausea, vomiting, diarrhea, hand-and-foot syndrome, anemia, weight loss, cardiomyopathy, gout, and decreased renal function, which may limit the use of this medication.
      • Schauder D.M.
      • Kim J.
      • Nijhawan R.I.
      Evaluation of the use of capecitabine for the treatment and prevention of actinic keratoses, squamous cell carcinoma, and basal cell carcinoma: a systematic review.
      • Jirakulaporn T.
      • Endrizzi B.
      • Lindgren B.
      • Mathew J.
      • Lee P.K.
      • Dudek A.Z.
      Capecitabine for skin cancer prevention in solid organ transplant recipients.
      • Endrizzi B.
      • Ahmed R.L.
      • Ray T.
      • Dudek A.
      • Lee P.
      Capecitabine to reduce nonmelanoma skin carcinoma burden in solid organ transplant recipients.

      Future and Novel Approaches

      Future investigations include evaluating the role of HPV vaccination in the prevention and treatment of SCC. Human papillomavirus has been associated with NMSC development, with HPV DNA found in 80% of NMSCs in immunosuppressed patients, including 50.9% to 93.3% of SCCs.
      • Ramezani M.
      • Baharzadeh F.
      • Almasi A.
      • Sadeghi M.
      A systematic review and meta-analysis: evaluation of the β-human papillomavirus in immunosuppressed individuals with cutaneous squamous cell carcinoma.
      Currently available HPV vaccines are efficacious in preventing high-risk HPV infection associated with cervical, anogenital, and oropharyngeal cancer in addition to providing partial cross-protection against other HPV types. Novel vaccines that offer cross-activity against other HPV types are under development and may help prevent development of SCC in SOTRs.
      • Herrero R.
      Human papillomavirus (HPV) vaccines: limited cross-protection against additional HPV types.
      T4 endonuclease V (T4N5) is an enzyme involved in DNA repair after exposure to UV radiation with a current study investigating the efficacy and safety of T4N5 lotion in the prevention of NMSC in SOTRs. Clinical trials investigating afamelanotide, a synthetic α-melanocyte–stimulating hormone, and the development of keratinocyte carcinomas in SOTRs are also ongoing.
      • Blomberg M.
      • He S.Y.
      • Harwood C.
      • et al.
      Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.
      Immune checkpoint inhibitors are a potential treatment option for metastatic or locally advanced skin cancer in SOTRs; however, they carry a substantial risk of transplanted organ rejection. Furthermore, there is not a validated protocol for balancing the immunosuppression required in organ transplant with the heightened immune activity caused by ICIs. A systematic review of organ transplant recipients who received treatment with ICIs, including PD-1, programmed death ligand 1, and cytotoxic lymphocyte antigen 4 inhibitors, reported an overall transplanted organ rejection rate of 41% and transplanted organ failure in 71% of those patients who experienced rejection. Risk was lowest with ipilimumab (23%) and highest with PD-1 inhibitors, including nivolumab (54%) and pembrolizumab (39%).
      • Kumar V.
      • Shinagare A.B.
      • Rennke H.G.
      • et al.
      The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature.
      A case series by Danesh et al
      • Danesh M.J.
      • Mulvaney P.M.
      • Murakami N.
      • et al.
      Impact of corticosteroids on allograft protection in renal transplant patients receiving anti-PD-1 immunotherapy.
      suggested that peri-infusional corticosteroid administration (pulsed corticosteroids around the time of ICI infusion or low-dose corticosteroid treatment after infusion) may be a promising therapy to prevent transplant rejection. The substantial risk of transplanted organ rejection and loss should be discussed with patients before initiation of treatment with ICIs. At this time, these medications are typically reserved for patients who have failed to respond to all other treatment options.
      Several smaller trials reported some additional possibilities for future direction of care. A pilot trial looking at a small cohort of lung transplant recipients randomly assigned to supplementation with omega-3 fatty acid or placebo found some promise in using omega-3 fatty acid supplementation in skin cancer prevention.
      • Miura K.
      • Vail A.
      • Chambers D.
      • et al.
      Omega-3 fatty acid supplement skin cancer prophylaxis in lung transplant recipients: a randomized, controlled pilot trial.
      Novel topical therapies containing DNA repair enzymes may be effective in AK treatment in SOTRs; however, better results were observed in immunocompetent patients than in SOTRs (54.7% reduction in mean number of AKs in immunocompetent patients compared with 36.7% among SOTRs).
      • Veronese F.
      • Zavattaro E.
      • Orioni G.
      • et al.
      Efficacy of new class I medical device for actinic keratoses: a randomized controlled prospective study.

      Conclusion

      A cornerstone of long-term survival after organ transplantation is skin cancer prevention and treatment, which warrants attention from all clinicians involved in the care of SOTRs. The nondermatologist should be familiar with prevention and treatment modalities for skin cancer and precancerous lesions and their unique risks and varied efficacy in SOTRs compared with immunocompetent patients. Patients should be encouraged to exercise skin cancer prevention strategies and to follow up regularly with a dermatologist. As our SOTR population grows and ages, future prospective research targeting SOTR-specific skin cancer treatment is needed to guide our care of this unique population. Although not yet standard of care, future novel medications, supplements, and vaccination may become a mainstay of prevention and treatment.

      Potential Competing Interests

      Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. Dr. Poland provides consultative advice to AiZtech; AstraZeneca UK Limited; Eli Lilly and Company; Emergent Biosolutions; Exelixis, Inc.; Genevant Sciences, Inc.; GlaxoSmithKline; Janssen Global Services, LLC; Medicago USA; Merck & Co. Inc.; Moderna; Novavax; Pfizer-BNT; Regeneron Pharmaceuticals, Inc.; Sanofi; Syneos Health; and Vyriad. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. Dr. Poland holds patents related to vaccinia, influenza, and measles peptide vaccines. Dr. Poland has received grant funding from ICW Ventures for preclinical studies on a peptide-based COVID-19 vaccine. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. Dr. Poland is an adviser to the White House and World Health Organization on Covid-19 vaccines and monkeypox.

      Acknowledgments

      The authors would like to thank James H. Keeling III, MD, from the department of Dermatology at Mayo Clinic Florida for providing clinical images E (Merkel cell carcinoma) and F (Kaposi sarcoma).

      References

        • Infusino S.D.
        • Loi C.
        • Ravaioli G.M.
        • Piraccini B.M.
        • Bardazzi F.
        • Patrizi A.
        Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience.
        G Ital Dermatol Venereol. 2020; 155: 662-668
        • Chung E.Y.
        • Palmer S.C.
        • Strippoli G.F.
        Interventions to prevent nonmelanoma skin cancers in recipients of a solid organ transplant: systematic review of randomized controlled trials.
        Transplantation. 2019; 103: 1206-1215
        • Pinho A.
        • Gouveia M.
        • Cardoso J.C.
        • Xavier M.M.
        • Vieira R.
        • Alves R.
        Non-melanoma skin cancer in Portuguese kidney transplant recipients—incidence and risk factors.
        An Bras Dermatol. 2016; 91: 455-462
        • Garrett G.L.
        • Blanc P.D.
        • Boscardin J.
        • et al.
        Incidence of and risk factors for skin cancer in organ transplant recipients in the United States.
        JAMA Dermatol. 2017; 153 (Published correction appears in JAMA Dermatol. 2017;153(3):357): 296-303
        • Tufaro A.P.
        • Azoury S.C.
        • Crompton J.G.
        • et al.
        Rising incidence and aggressive nature of cutaneous malignancies after transplantation: an update on epidemiology, risk factors, management and surveillance.
        Surg Oncol. 2015; 24: 345-352
        • Gogia R.
        • Binstock M.
        • Hirose R.
        • Boscardin W.J.
        • Chren M.M.
        • Arron S.T.
        Fitzpatrick skin phototype is an independent predictor of squamous cell carcinoma risk after solid organ transplantation.
        J Am Acad Dermatol. 2013; 68: 585-591
        • Howard M.D.
        • Su J.C.
        • Chong A.H.
        Skin cancer following solid organ transplantation: a review of risk factors and models of care.
        Am J Clin Dermatol. 2018; 19: 585-597
        • Fattouh K.
        • Ducroux E.
        • Decullier E.
        • et al.
        Increasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study.
        Transpl Int. 2017; 30: 1172-1180
        • Werner R.N.
        • Sammain A.
        • Erdmann R.
        • Hartmann V.
        • Stockfleth E.
        • Nast A.
        The natural history of actinic keratosis: a systematic review.
        Br J Dermatol. 2013; 169: 502-518
        • Fuchs A.
        • Marmur E.
        The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma.
        Dermatol Surg. 2007; 33: 1099-1101
        • Poulin Y.
        • Lynde C.W.
        • Barber K.
        • et al.
        Non-melanoma skin cancer in Canada chapter 3: management of actinic keratoses.
        J Cutan Med Surg. 2015; 19 (Published correction appears in J Cutan Med Surg. 2015;19(6):604): 227-238
        • Bruce A.J.
        • Brodland D.G.
        Overview of skin cancer detection and prevention for the primary care physician.
        Mayo Clin Proc. 2000; 75: 491-500
        • Manyam B.V.
        • Gastman B.
        • Zhang A.Y.
        • et al.
        Inferior outcomes in immunosuppressed patients with high-risk cutaneous squamous cell carcinoma of the head and neck treated with surgery and radiation therapy.
        J Am Acad Dermatol. 2015; 73: 221-227
        • Bibee K.
        • Swartz A.
        • Sridharan S.
        • et al.
        Cutaneous squamous cell carcinoma in the organ transplant recipient.
        Oral Oncol. 2020; 103104562
        • Puza C.J.
        • Beasley G.M.
        • Barbas A.S.
        • Mosca P.J.
        Type of organ transplanted impacts the risk and presentation of cutaneous squamous cell carcinoma in transplant recipients.
        Exp Clin Transplant. 2020; 18: 93-97
        • Blomberg M.
        • He S.Y.
        • Harwood C.
        • et al.
        Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.
        Br J Dermatol. 2017; 177: 1225-1233
        • Karia P.S.
        • Jambusaria-Pahlajani A.
        • Harrington D.P.
        • Murphy G.F.
        • Qureshi A.A.
        • Schmults C.D.
        Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital Tumor Staging for cutaneous squamous cell carcinoma.
        J Clin Oncol. 2014; 32: 327-334
        • Blechman A.B.
        • Carucci J.A.
        • Stevenson M.L.
        Stratification of poor outcomes for cutaneous squamous cell carcinoma in immunosuppressed patients using the American Joint Committee on Cancer Eighth Edition and Brigham and Women’s Hospital staging systems.
        Dermatol Surg. 2019; 45: 1117-1124
        • Otley C.C.
        • Berg D.
        • Ulrich C.
        • et al.
        Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey.
        Br J Dermatol. 2006; 154: 395-400
        • Abdel-Wahab N.
        • Safa H.
        • Abudayyeh A.
        • et al.
        Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature.
        J Immunother Cancer. 2019; 7 (Published correction appears in J Immunother Cancer. 2019;7(1):158): 106
        • Murakami N.
        • Mulvaney P.
        • Danesh M.
        • et al.
        A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.
        Kidney Int. 2021; 100: 196-205
        • Kim J.Y.
        • Kozlow J.H.
        • Mittal B.
        • et al.
        Guidelines of care for the management of basal cell carcinoma.
        J Am Acad Dermatol. 2018; 78: 540-559
        • Rahatli S.
        • Oguz A.
        • Altundag O.
        • Haberal M.
        Vismodegib experience in a renal transplant patient with basal cell carcinoma.
        Exp Clin Transplant. Published online June 2, 2020; https://doi.org/10.6002/ect.2019.0293
        • Cusack C.A.
        • Nijhawan R.
        • Miller B.
        • et al.
        Vismodegib for locally advanced basal cell carcinoma in a heart transplant patient.
        JAMA Dermatol. 2015; 151: 70-72
        • Koelblinger P.
        • Dummer R.
        • Laimer M.
        • et al.
        Vismodegib for recurrent locally destructive basal cell carcinoma in a renal transplant patient.
        J Eur Acad Dermatol Venereol. 2018; 32: e7-e8
        • Stratigos A.J.
        • Sekulic A.
        • Peris K.
        • et al.
        Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.
        Lancet Oncol. 2021; 22: 848-857
        • Damsin T.
        • Lebas E.
        • Marchal N.
        • Rorive A.
        • Nikkels A.F.
        Cemiplimab for locally advanced and metastatic basal cell carcinoma.
        Expert Rev Anticancer Ther. 2022; 22: 243-248
        • Vajdic C.M.
        • Chong A.H.
        • Kelly P.J.
        • et al.
        Survival after cutaneous melanoma in kidney transplant recipients: a population-based matched cohort study.
        Am J Transplant. 2014; 14: 1368-1375
        • Chan W.H.
        • Tsao H.
        Consensus, controversy, and conversations about gene expression profiling in melanoma.
        JAMA Dermatol. 2020; 156: 949-951
        • Hanson J.
        • Demer A.
        • Liszewski W.
        • Foman N.
        • Maher I.
        Improved overall survival of melanoma of the head and neck treated with Mohs micrographic surgery versus wide local excision.
        J Am Acad Dermatol. 2020; 82: 149-155
        • Zwald F.O.
        • Christenson L.J.
        • Billingsley E.M.
        • et al.
        Melanoma in solid organ transplant recipients.
        Am J Transplant. 2010; 10: 1297-1304
        • Mittal A.
        • Colegio O.R.
        Skin cancers in organ transplant recipients.
        Am J Transplant. 2017; 17: 2509-2530
        • Nguyen L.S.
        • Ortuno S.
        • Lebrun-Vignes B.
        • et al.
        Transplant rejections associated with immune checkpoint inhibitors: a pharmacovigilance study and systematic literature review.
        Eur J Cancer. 2021; 148: 36-47
        • Kumar V.
        • Shinagare A.B.
        • Rennke H.G.
        • et al.
        The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature.
        Oncologist. 2020; 25: 505-514
        • Becker J.C.
        Merkel cell carcinoma.
        Ann Oncol. 2010; 21: vii81-vii85
        • Feng H.
        • Shuda M.
        • Chang Y.
        • Moore P.S.
        Clonal integration of a polyomavirus in human Merkel cell carcinoma.
        Science. 2008; 319: 1096-1100
        • Zanetti I.
        • Coati I.
        • Alaibac M.
        Interaction between Merkel cell carcinoma and the immune system: pathogenetic and therapeutic implications.
        Mol Clin Oncol. 2017; 7: 729-732
        • Bradford D.
        • Demko S.
        • Jin S.
        • et al.
        FDA accelerated approval of pembrolizumab for recurrent locally advanced or metastatic Merkel cell carcinoma.
        Oncologist. 2020; 25: e1077-e1082
        • Maggiore U.
        • Pascual J.
        The bad and the good news on cancer immunotherapy: implications for organ transplant recipients.
        Adv Chronic Kidney Dis. 2016; 23: 312-316
        • Delyon J.
        • Rabate C.
        • Euvrard S.
        • et al.
        Management of Kaposi sarcoma after solid organ transplantation: a European retrospective study.
        J Am Acad Dermatol. 2019; 81: 448-455
        • Hosseini-Moghaddam S.M.
        • Soleimanirahbar A.
        • Mazzulli T.
        • Rotstein C.
        • Husain S.
        Post renal transplantation Kaposi’s sarcoma: a review of its epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy.
        Transpl Infect Dis. 2012; 14: 338-345
        • Casper C.
        New approaches to the treatment of human herpesvirus 8–associated disease.
        Rev Med Virol. 2008; 18: 321-329https://doi.org/10.1002/rmv.583
        • Crow L.D.
        • Jambusaria-Pahlajani A.
        • Chung C.L.
        • et al.
        Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.
        Transpl Int. 2019; 32: 1268-1276
        • Acuna S.A.
        • Huang J.W.
        • Scott A.L.
        • et al.
        Cancer screening recommendations for solid organ transplant recipients: a systematic review of clinical practice guidelines.
        Am J Transplant. 2017; 17: 103-114
        • Chan A.W.
        • Fung K.
        • Austin P.C.
        • et al.
        Improved keratinocyte carcinoma outcomes with annual dermatology assessment after solid organ transplantation: population-based cohort study.
        Am J Transplant. 2019; 19: 522-531
        • Nadhan K.S.
        • Larijani M.
        • Abbott J.
        • Doyle A.M.
        • Linfante A.W.
        • Chung C.L.
        Prevalence and types of genital lesions in organ transplant recipients.
        JAMA Dermatol. 2018; 154: 323-329
        • Mihalis E.L.
        • Wysong A.
        • Boscardin W.J.
        • Tang J.Y.
        • Chren M.M.
        • Arron S.T.
        Factors affecting sunscreen use and sun avoidance in a U.S. national sample of organ transplant recipients.
        Br J Dermatol. 2013; 168: 346-353
        • James L.J.
        • Saglimbene V.
        • Wong G.
        • et al.
        Behavioural and pharmaceutical interventions for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomised controlled trials.
        BMJ Open. 2020; 10e029265
        • Wu S.Z.
        • Jiang P.
        • DeCaro J.E.
        • Bordeaux J.S.
        A qualitative systematic review of the efficacy of sun protection education in organ transplant recipients.
        J Am Acad Dermatol. 2016; 75: 1238-1244.e5
        • Jiyad Z.
        • Olsen C.M.
        • Burke M.T.
        • Isbel N.M.
        • Green A.C.
        Azathioprine and risk of skin cancer in organ transplant recipients: systematic review and meta-analysis.
        Am J Transplant. 2016; 16: 3490-3503
        • Londoño M.C.
        • Rimola A.
        • O’Grady J.
        • Sanchez-Fueyo A.
        Immunosuppression minimization vs. complete drug withdrawal in liver transplantation.
        J Hepatol. 2013; 59: 872-879
        • Murray S.L.
        • Daly F.E.
        • O’Kelly P.
        • et al.
        The impact of switching to mTOR inhibitor–based immunosuppression on long-term non-melanoma skin cancer incidence and renal function in kidney and liver transplant recipients.
        Ren Fail. 2020; 42: 607-612
        • Alberú J.
        • Pascoe M.D.
        • Campistol J.M.
        • 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: 303-310
        • Dantal J.
        • Morelon E.
        • Rostaing L.
        • et al.
        Sirolimus for secondary prevention of skin cancer in kidney transplant recipients: 5-year results.
        J Clin Oncol. 2018; 36: 2612-2620
        • Funk-Debleds P.
        • Ducroux E.
        • Guillaud O.
        • et al.
        Subsequent nonmelanoma skin cancers and impact of immunosuppression in liver transplant recipients.
        J Am Acad Dermatol. 2018; 79: 84-91
        • Karia P.S.
        • Azzi J.R.
        • Heher E.C.
        • Hills V.M.
        • Schmults C.D.
        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
        • Yanik E.L.
        • Siddiqui K.
        • Engels E.A.
        Sirolimus effects on cancer incidence after kidney transplantation: a meta-analysis.
        Cancer Med. 2015; 4: 1448-1459
        • Knoll G.A.
        • Kokolo M.B.
        • Mallick R.
        • et al.
        Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.
        BMJ. 2014; 349 (Published correction appears in BMJ. 2014;349:g7543): g6679
        • Euvrard S.
        • Morelon E.
        • Rostaing L.
        • et al.
        Sirolimus and secondary skin-cancer prevention in kidney transplantation.
        N Engl J Med. 2012; 367: 329-339
        • Gu Y.H.
        • Du J.X.
        • Ma M.L.
        Sirolimus and non-melanoma skin cancer prevention after kidney transplantation: a meta-analysis.
        Asian Pac J Cancer Prev. 2012; 13: 4335-4339
        • Phan K.
        • Moloney F.J.
        • Hogarty D.T.
        • Lenane P.
        • McColl D.
        • Yazdabadi A.
        Mammalian target of rapamycin (mTOR) inhibitors and skin cancer risk in nonrenal solid organ transplant recipients: systematic review and meta-analysis.
        Int J Dermatol. 2020; 59: 91-98
        • Badve S.V.
        • Pascoe E.M.
        • Burke M.
        • et al.
        Mammalian target of rapamycin inhibitors and clinical outcomes in adult kidney transplant recipients.
        Clin J Am Soc Nephrol. 2016; 11: 1845-1855
        • Alter M.
        • Satzger I.
        • Schrem H.
        • Kaltenborn A.
        • Kapp A.
        • Gutzmer R.
        Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR-inhibitors in organ transplant recipients.
        J Dtsch Dermatol Ges. 2014; 12: 480-488
        • Hoogendijk-van den Akker J.M.
        • Harden P.N.
        • Hoitsma A.J.
        • 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
        • Campbell S.B.
        • Walker R.
        • Tai S.S.
        • Jiang Q.
        • Russ G.R.
        Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer.
        Am J Transplant. 2012; 12: 1146-1156
        • Aguiar D.
        • Martínez-Urbistondo D.
        • Baroja-Mazo A.
        • et al.
        Real-world multicenter experience of immunosuppression minimization among 661 liver transplant recipients.
        Ann Transplant. 2017; 22: 265-275
        • Coghill A.E.
        • Johnson L.G.
        • Berg D.
        • Resler A.J.
        • Leca N.
        • Madeleine M.M.
        Immunosuppressive medications and squamous cell skin carcinoma: nested case-control study within the skin cancer after organ transplant (SCOT) cohort.
        Am J Transplant. 2016; 16: 565-573
        • Feist A.
        • Lee R.
        • Osborne S.
        • Lane J.
        • Yung G.
        Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole.
        J Heart Lung Transplant. 2012; 31: 1177-1181
        • Heppt M.V.
        • Steeb T.
        • Niesert A.C.
        • et al.
        Local interventions for actinic keratosis in organ transplant recipients: a systematic review.
        Br J Dermatol. 2019; 180: 43-50
        • Mann M.
        • Berk D.R.
        • Petersen J.
        Chemowraps as an adjuvant to surgery for patients with diffuse squamous cell carcinoma of the extremities.
        J Drugs Dermatol. 2008; 7: 685-688
        • Blauvelt A.
        • Kempers S.
        • Lain E.
        • et al.
        Phase 3 trials of tirbanibulin ointment for actinic keratosis.
        N Engl J Med. 2021; 384: 512-520
        • Braathen L.R.
        • Szeimies R.M.
        • Basset-Seguin N.
        • et al.
        Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus.
        J Am Acad Dermatol. 2007; 56 (125-1)
        • Liew Y.C.
        • de Souza N.N.
        • Sultana R.G.
        • Oh C.C.
        Photodynamic therapy for the prevention and treatment of actinic keratosis/squamous cell carcinoma in solid organ transplant recipients: a systematic review and meta-analysis.
        J Eur Acad Dermatol Venereol. 2020; 34: 251-259
        • Morton C.A.
        A synthesis of the world’s guidelines on photodynamic therapy for non-melanoma skin cancer.
        G Ital Dermatol Venereol. 2018; 153: 783-792
        • Bernad I.
        • Aguado L.
        • Núñez-Córdoba J.M.
        • Redondo P.
        Daylight photodynamic therapy for prevention of new actinic keratosis and keratinocyte carcinomas in organ transplants. A cryotherapy-controlled randomized clinical trial.
        J Eur Acad Dermatol Venereol. 2020; 34: 1464-1470
        • Togsverd-Bo K.
        • Lei U.
        • Erlendsson A.M.
        • et al.
        Combination of ablative fractional laser and daylight-mediated photodynamic therapy for actinic keratosis in organ transplant recipients—a randomized controlled trial.
        Br J Dermatol. 2015; 172: 467-474
        • Tee L.Y.
        • Sultana R.
        • Tam S.Y.
        • Oh C.C.
        Chemoprevention of keratinocyte carcinoma and actinic keratosis in solid-organ transplant recipients: systematic review and meta-analyses.
        J Am Acad Dermatol. 2021; 84: 528-530
        • Herold M.
        • Good A.J.
        • Nielson C.B.
        • Longo M.I.
        Use of topical and systemic retinoids in solid organ transplant recipients.
        Dermatol Surg. 2019; 45: 1442-1449
        • Drago F.
        • Ciccarese G.
        • Cogorno L.
        • Calvi C.
        • Marsano L.A.
        • Parodi A.
        Prevention of non-melanoma skin cancers with nicotinamide in transplant recipients: a case-control study.
        Eur J Dermatol. 2017; 27: 382-385
        • Schauder D.M.
        • Kim J.
        • Nijhawan R.I.
        Evaluation of the use of capecitabine for the treatment and prevention of actinic keratoses, squamous cell carcinoma, and basal cell carcinoma: a systematic review.
        JAMA Dermatol. 2020; 156: 1117-1124
        • Jirakulaporn T.
        • Endrizzi B.
        • Lindgren B.
        • Mathew J.
        • Lee P.K.
        • Dudek A.Z.
        Capecitabine for skin cancer prevention in solid organ transplant recipients.
        Clin Transplant. 2011; 25: 541-548
        • Endrizzi B.
        • Ahmed R.L.
        • Ray T.
        • Dudek A.
        • Lee P.
        Capecitabine to reduce nonmelanoma skin carcinoma burden in solid organ transplant recipients.
        Dermatol Surg. 2013; 39: 634-645
        • Ramezani M.
        • Baharzadeh F.
        • Almasi A.
        • Sadeghi M.
        A systematic review and meta-analysis: evaluation of the β-human papillomavirus in immunosuppressed individuals with cutaneous squamous cell carcinoma.
        Biomedicine (Taipei). 2020; 10: 1-10
        • Herrero R.
        Human papillomavirus (HPV) vaccines: limited cross-protection against additional HPV types.
        J Infect Dis. 2009; 199: 919-922
        • Danesh M.J.
        • Mulvaney P.M.
        • Murakami N.
        • et al.
        Impact of corticosteroids on allograft protection in renal transplant patients receiving anti-PD-1 immunotherapy.
        Cancer Immunol Immunother. 2020; 69: 1937-1941
        • Miura K.
        • Vail A.
        • Chambers D.
        • et al.
        Omega-3 fatty acid supplement skin cancer prophylaxis in lung transplant recipients: a randomized, controlled pilot trial.
        J Heart Lung Transplant. 2019; 38: 59-65
        • Veronese F.
        • Zavattaro E.
        • Orioni G.
        • et al.
        Efficacy of new class I medical device for actinic keratoses: a randomized controlled prospective study.
        J Dermatolog Treat. 2021; 32: 625-630