SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 714 BRIEF ARTICLE Characterizing Skin Cancers Arising for the First Time Following Solid Organ Transplant with Subsequent Recurrence Chelsea Shope, MSCR1, Laura Andrews, MSCR1, Courtney Linkous, BA1, Ashley Girvin, BS1, Hannah Neimy, BS1, Lara Wine Lee, MD, PhD2 1 College of Medicine, Medical University of South Carolina, Charleston, SC 2 Department of Dermatology & Dermatologic Surgery, Medical University of South Carolina, Charleston, SC There is an established relationship between solid organ transplantation (SOT) and increased incidence of skin cancers.1 Exposure to ultraviolet A (UVA, 280 – 315 nm) and ultraviolet B (UVB, 315 – 400 nm) radiation significantly increases risk of developing keratinocyte carcinoma (KC) and malignant melanoma (MM) by promoting DNA damage and stimulating inflammation.2 In patients receiving immunosuppressive treatment necessary to prevent graft rejection following any transplant, natural immunosurveillance mechanisms are inhibited.2 Thus, there is an observed association between chronic immunosuppression and increased carcinogenesis as well as persistence of oncogenic viral infections.3 In patients diagnosed with either KC or MM prior to organ transplantation, there have been observed increases in both mortality and recurrence,4 however, little is known regarding skin cancers which arise for the ABSTRACT Introduction: There is an established relationship between solid organ transplantation (SOT) and increased incidence of skin cancers. There is a paucity of data characterizing skin cancers arising for the first-time post-transplant that subsequently recur. Methods: We conducted a retrospective review to identify SOT recipients (SOTRs) at our institution with recurrence of skin cancer that initially developed post-transplant (“recurrence”). Patients with pre-transplant history of skin cancer were excluded. Data was analyzed using one-sample t-tests. Results: Of 530 SOTRs identified, 33 had recurrence (mean 3.97 + 6.97). SOTRs with recurrence were male (87.9%), white (97%), renal recipients (75.7%) with a mean age at transplant of 56.52 [+11.69] years (p-value<0.001 each). Recurrences arose from SCC (66.7%) on the face or scalp (57.5%), which were invasive at time of diagnosis (63.6%) (p- value<0.001 each). Conclusion: In our cohort, white renal and cardiac transplants and a history of smoking appear to have a higher risk for recurrence of de novo post-transplant skin cancers. Our data supports that all SOTRs should have close and routine dermatologic follow-up due to risk for skin malignancy, which are disproportionately high-risk and invasive at the time of presentation. INTRODUCTION SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 715 first-time post-transplant and subsequently recur. We aimed to further characterize the incidence of such recurrences in SOT recipients (SOTRs). After IRB approval was received by the Medical University of South Carolina (IRB-I, Pro00120456), a retrospective review was conducted to identify SOTRs at our institution who were seen within a dermatology clinic. Patients who had a history of skin cancer prior to transplant were excluded. Demographic data and information regarding transplant and dermatologic course were collected. Patients were then stratified by presence of any skin cancer arising for the first-time post-transplant, and then further divided by subsequent recurrence of post- transplant skin cancers (hereafter referred to as recurrence). Data was analyzed using one-sample t-tests. Between January 1, 2012, and June 1, 2022, 530 SOTRs were seen within a dermatology clinic. The majority were white (63.58%) and male (70.19%), with a mean age of 49.44 years at time of transplant. Among SOTRs, 203 patients (38.3%) developed 1,641 skin cancers for the first-time following transplant, which included KC, MM, Merkel cell carcinoma (MCC), and porocarcinoma. SOTRs with cancerous lesions were white (95.1%), male (72.9%), renal transplant recipients (64.0%) with a mean age of 54.33 [+11.52] years at transplant. A total of 33 patients experienced at least 1 recurrence arising from a de novo post- transplant skin cancer (mean 3.97 + 6.97). Patients with recurrence were most often male (87.9%, p-value<0.001), white (97%, p- value<0.001), renal transplant recipients (75.7%, p-value<0.001) with a mean age at transplant of 56.52 [+11.69] years. Slightly over half of patients are currently living (57.6%). Patients were also likely to be current or former smokers (57.6%, (p- value<0.001) (Table 1). Significant comorbid conditions include hypertension (p-value<0.001), type 2 diabetes (p-value=0.002), hyperlipidemia (p- value<0.001), chronic kidney disease/end stage renal disease (p-value<0.001), and cardiomyopathy or coronary artery disease (p-value<0.001) (Table 1). Risk factors for recurrence include family history of skin cancer (p-value=0.006), heart transplant (p- value=0.006), and the use of post-transplant meds including tacrolimus (p-value<0.001), cyclosporine (p-value=0.006), mycophenolate mofetil (MMF) (p- value<0.001), and prednisone ((p- value<0.001) (Table 2). First skin cancers were most commonly SCC (66.7%, p-value<0.001), and invasive at time of diagnosis (63.6%, p-value<0.001), of which half were high risk (50%, p- value=0.006). Subsequent skin cancers were most often SCC (69.7%, p-value<0.001). Skin cancers most frequently developed on the face or scalp (57.5%, p-value<0.001) (Table 2). Given improvements made in post-transplant mortality rates with standardized immunosuppressive therapies, patients are living longer and incidence of post-transplant morbidities such as cutaneous malignancies are increased.1 Skin cancers account for approximately 40% of all post-transplant malignancies. In fact, it is estimated that as METHODS RESULTS DISCUSSION SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 716 Table 1. Patient demographics of organ transplant recipients with first skin cancer occurring post-transplant, with subsequent recurrence. All SOTRs (n=530) SOTRs with Post- transplant Skin Cancer (n=203) SOTRs with Recurrent Post- Transplant Skin Cancer (n=33) p-value Age at transplant (mean, SD) 49.44 [+16] 54.33 [+11.52] 56.52 [+11.69] <0.001* Race (n, %) <0.001* African American 177 (33.4%) 7 (3.4%) 0 (0%) American Indian/Alaska Native 2 (0.4%) 1 (0.5%) 0 (0%) Asian 7 (1.3%) 0 (0%) 0 (0%) Caucasian 337 (63.6%) 193 (95.1%) 32 (97%) Hispanic or Latino 5 (0.9%) 1 (0.5%) 1 (3.0%) Pacific Islander 1 (0.2%) 0 (0%) 0 (0%) Other 1 (0.2%) 1 (0.5%) 0 (0%) Sex (n, %) <0.001* Female 372 (70.2%) 148 (72.9%) 4 (12.1%) Male 203 (29.8%) 55 (27.1%) 29 (87.9%) Transplant type (n, %)+ <0.001* Renal 374 (70.6%) 130 (64.0%) 25 (75.7%) Liver 80 (15.1%) 37 (18.2%) 1 (3.0%) Heart 85 (16.0%) 45 (22.2%) 7 (21.2%) Lung 16 (3.0%) 10 (4.9%) 2 (6.1%) Pancreas 49 (9.2%) 21 (10.3%) 1 (3.0%) Smoking Status <0.001* Never Smoker 270 (50.9%) 78 (38.4%) 14 (42.4%) Current Smoker 18 (3.4%) 7 (3.4%) 1 (3.0%) Former Smoker 242 (45.7%) 118 (58.1%) 18 (54.5%) Comorbid Conditions Hypertension 397 (74.9%) 146 (71.9%) 23 (69.7%) <0.001* Type 2 Diabetes Mellitus 187 (35.3%) 59 (29.1%) 9 (27.3%) 0.002 Hyperlipidemia 198 (37.4%) 86 (42.4%) 14 (42.4%) <0.001* CKD/ESRD 289 (54.5%) 100 (49.3%) 21 (63.6%) <0.001* Cardiomyopathy/CAD 143 (27.0%) 55 (27.1%) 10 (30.3%) <0.001* SOTR: Solid organ transplant recipient CKD: Chronic kidney disease ESRD: End-stage renal disease *Indicates statistically significant result (p-value <0.05) +Patients may have received more than one organ type SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 717 Table 2. Risk factors for skin cancer recurrence in organ transplant recipients with skin cancer arising for the first-time post-transplant. SOTRs with Recurrent Skin Cancer (n = 33) p-value Family History of skin cancer 0.006* Post-transplant Medications (n, %) Tacrolimus 25 (75.8%) <0.001* Cyclosporine 7 (21.2%) 0.006* Mycophenolate mofetil 18 (54.5%) <0.001* Prednisone 27 (81.8%) <0.001* Type of First Skin Cancer (n, %) Squamous Cell Carcinoma 22 (66.7%) <0.001* SCCis* 7 (31.8%) 0.006* Invasive+ 14 (63.6%) <0.001* Low risk 4 (28.6%) High risk 7 (50.0%) Very high risk 4 (28.6%) Basal Cell Carcinoma 11 (33.3%) <0.001* Melanoma in situ 1 (3.0%) 0.325 Location of Skin Cancer (n, %) <0.001* Scalp 8 (24.2%) Face 12 (36.4%) Neck 2 (6.1%) Chest or back 3 (9.1%) Upper Extremities 5 (15.2%) Lower Extremities 2 (6.1%) Unknown 1 (3.0%) Total Number of Skin Cancers (n) n = 412 Squamous Cell Carcinoma 269 (65.3%) Basal Cell Carcinoma 138 (33.5%) Malignant Melanoma 5 (1.2%) *SCCis: Squamous Cell Carcinoma in situ. **Indicates statistically significant result (p-value <0.05) +Low risk: trunk/extremities, <2 cm OR well/moderately differentiated, <6 mm deep. High risk: trunk/extremities, 2 -4 cm OR anywhere on head/neck. Very high risk: any site >4 cm OR poorly differentiated, >6 mm deep, or perineural/lymphatic involvement. SKIN March 2023 Volume 7 Issue 2 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 718 many as 70% of patients with lower Fitzpatrick phototypes (I or II) will be diagnosed with a skin cancer within 20 years following transplant.5 Among our cohort, there was a correlation between white patients, who tend to have Fitzpatrick phototypes I or II, and a higher risk for recurrence of skin cancers that arose for the first time post-transplant, in the absence of a pre-transplant history of skin cancer. Other risks factors correlated with recurrence among our cohort included renal or cardiac transplant, smoking status, and family history of skin cancer. Common transplant medications such as tacrolimus, cyclosporine, MMF, and prednisone were also correlated with increased risk for skin cancer recurrence. It is evident that regular practice of skin cancer prevention strategies is critical for immunosuppressed patients.1 Transplant recipients should perform monthly cutaneous self-examinations. As SOTRs are high-risk for post-transplant skin cancer, which are disproportionately high-risk and invasive at the time of diagnosis, transplant recipients should have regular and close examinations performed by a dermatologist. Additionally, a potential modification of the immunosuppressive treatment regimen should be considered should skin cancer arise.4 Conflict of Interest Disclosures: None Funding: None Corresponding Author: Chelsea Shope, MSCR 135 Rutledge Ave, 11th Floor Charleston, SC 29425 Email: shopec@musc.edu References: 1. Collins L, Quinn A, Stasko T. Skin Cancer and Immunosuppression. Dermatol Clin. 2019;37(1):83-94. 2. Moyal DD, Fourtanier AM. Broad-spectrum sunscreens provide better protection from solar ultraviolet-simulated radiation and natural sunlight-induced immunosuppression in human beings. J Am Acad Dermatol. 2008;58(5 Suppl 2):S149-154. 3. Nindl I, Rösl F. Molecular concepts of virus infections causing skin cancer in organ transplant recipients. Am J Transplant. 2008;8(11):2199-2204. 4. O'Reilly Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65(2):253-261. 5. Baldwin S, Au S. One-Year Review of the SCREEN (Skin Cancer Post-Transplant) Clinic. J Cutan Med Surg. 2017;21(1):80-81. CONCLUSION