Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2023;13(3):e2023065 1 Impact of UV Modifying Factors on the Incidence of Keratinocyte Carcinomas in Solid Organ Transplant Recipients: A Systematic Review Syed Minhaj Rahman1, Fahad Ahmed2, Amir Amanullah3, Adel Haque4 1 Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, New York 2 Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 3 Department of Dermatology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 4 Department of Medicine, Jefferson Health Northeast, Philadelphia, Pennsylvania Key words: keratinocyte, organ transplant recipient, ultraviolet radiation, Fitzpatrick Skin Type, sun exposure Citation: Rahman SM, Ahmed F, Amanullah A, Haque A. Impact of UV Modifying Factors on the Incidence of Keratinocyte Carcinomas in Solid Organ Transplant Recipients: A Systematic Review. Dermatol Pract Concept. 2023;13(3):e2023065. DOI: https://doi.org/10.5826/dpc.1303a65 Accepted: January 11, 2023; Published: July 2023 Copyright: ©2023 Rahman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding author: Syed Minhaj Rahman, BA, Department of Dermatology, University of Rochester School of Medicine and Dentistry, 1188 Mount Hope Ave, Apt 503 Rochester, NY 14620 Telephone: (718)-598-4637 E-mail: minhaj_rahman@urmc.rochester.edu Introduction: Solid organ transplant recipients (SOTR) are at an increased risk for developing kerati- nocyte carcinomas (KC). Four ultraviolet (UV) modifying factors have been identified that impact the incidence of KC: Fitzpatrick Skin Type (FST), race, sun exposure, and sun-protective factors. Objectives: We conducted a systematic review to summarize the association between UV modifying factors and the incidence of KC in SOTR. Methods: We systematically searched PubMed, Scopus, and Web of Science databases, and after screening for inclusion and exclusion criteria, we included 13 studies with 6,910 solid organ transplant recipients in our analysis. Results: Our review found that lower FST (I-II), white and Latinx populations, lack of regulated sunscreen application, and occupational and residential sun exposure are individual risk factors among solid organ transplant recipients for KC incidence. Although previous studies showed an in- creased SCC:BCC ratio, some studies found a contradictory increased BCC:SCC ratio. Limitations include few research studies that analyze these UV modifying factors and a lack of incorporating both varying immunosuppressant factors and transplantation follow-up times. Conclusions: These findings support the need for dermatological advice in increased risk patient demographic populations, lower FST and white and Latinx populations, and subsequently moderating sun exposure and protective factors. ABSTRACT 2 Review | Dermatol Pract Concept. 2023;13(3):e2023065 Introduction Keratinocyte carcinomas (KC) are non-melanoma skin can- cers (NMSC) consisting of basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) [1]. KCs are the most preva- lent cancer worldwide with 20-25% of KCs being SCC [2,3]. Solid organ transplant recipients (SOTR) have an increased risk of developing KC and these patients are at a 65-250 in- creased risk for cutaneous SCC than the general population [4-6]. Specifically, a recent Delphi consensus survey found that male thoracic organ recipients aged 50 or older at the time of transplant are at the highest risk for developing skin cancer [7]. There are several UV modifying factors that can impact KC incidence in SOTR, however, the 4 major vari- ables are: Fitzpatrick skin type (FST), race, sunscreen use, and sun exposure. The FST classifies 6 skin complexions and reactions to sun exposure ranging from very light skin, burns easily, and never tans (FST I) to very dark skin, never burns, and tans profusely (FST VI) [8]. Although there are overlapping factors in FST and race, several other factors should be ac- counted for such as: environmental, geographic, and socio- economic factors. All of these factors impact the association between race and KC incidence. Aside from FST, sun exposure and sun protective actions are major contributors to skin cancer incidence [9]. Sun ex- posure and sunburn can be used indirectly as tools to as- sess skin cancer risk as it accounts for UV exposure amount and skin sensitivity [10]. Although some studies show that continuously high sun exposure is more closely associated with an increase in SCC incidence, other studies have also reported a positive association between sunburn history and KC incidence [11-15]. Sunscreen is a primary photoprotective factor against UV radiation that absorbs environmental UV rays to pro- tect the skin [16]. A trial conducted in Queensland, Australia found that daily morning use of broad-spectrum sun protec- tion factor (SPF)-16 sunscreen on the head, neck, arms, and hands of healthy individuals decreased both the number of individuals with SCCs and the incidence of SCC tumors up to 8 years post-cessation of intervention [17]. However, this same protective factor for regular use of sunscreen was not significant in reducing BCC incidence. Objectives To the author best knowledge, there is a lack of systematic re- views that assess the impact of UV modifying factors on skin cancer incidence in the adult SOTR population. Although there is substantial evidence suggesting immunosuppression increases the risk of SOTR developing KC, this systematic re- view will synthesize the evidence from retrospective cohort, prospective cohort, case-control, and observational studies to summarize the association between UV modifying fac- tors and the incidence of KC in SOTR. The results of this study will help clinicians better assess what pertinent, signif- icant risk factors to be aware of when treating adult SOTR and monitoring for the development of KC. Results of this study will allow us to lead a discussion regarding skin phe- notype, race, and UV protection/exposure and better guide physicians treating SOTR adults. Methods Study Identification A systematic literature search using PubMed and Scopus databases was performed. This search included all years through April 2022 and consisted of the search terms: “ organ transplantation” OR “organ graft” OR “organ transplant recipients” AND “skin cancer” OR “squamous cell carcinomas” OR “basal cell carcinomas” OR “cutaneous squamous cell carcinoma” OR “nonmelanoma skin cancer” OR “keratinocyte carcinoma” AND “skin tone” OR “skin color” OR “Fitzpatrick skin type” OR “sunscreen” or “sun protective factors”. Additionally, we searched the reference lists of selected studies. The search was conducted adhering to the updated 2020 standards of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement [18]. Eligibility Criteria Two reviewers (SR and FA) selected studies that met the following inclusion criteria: i) the population of interest - adult solid organ transplant recipients, including FST or skin tone identification, race, sunscreen behaviors, or sun exposure; ii) the outcomes of interest - cutaneous squamous cell carcinomas, basal cell carcinomas, or non-melanoma skin cancers; and iii) observational or interventional study designs (cross-sectional studies, cohort studies, case stud- ies, cases series, or randomized controlled trials). Studies were excluded if there was no record of UV modifying risk factors. Any disagreement was resolved by a third re- viewer (AA). Data Extraction A total of 480 studies were screened and 13 were included. Information was collected on study design, data source, number of participants, selection criteria, and outcomes of interest including SCC, BCC, KC, and overall NMSC inci- dence based on our 4 UV modifying risk factors. FST and race data collected and analyzed is presented in Table 1. Sun exposure and sunscreen data collected and analyzed is pre- sented in Table 2. Review | Dermatol Pract Concept. 2023;13(3):e2023065 3 Ta b le 1 . St u d ie s ex am in in g ke ra ti n o cy te c ar ci n o m a ri sk v ar ia b le s, F it zp at ri ck s k in t yp e, a n d r ac e in s o li d o rg an t ra n sp la n t re ci p ie n ts . K C R is k V a ri a b le S tu d ie d S tu d y A u th o r( S ) A n d Y e a r P u b li sh e d S tu d y D e si g n D a ta C o ll e ct io n Lo ca ti o n ( Y e a r R a n g e s) N u m b e r o f S u b je ct s in S tu d y K C R e p o rt e d Ty p e o f Tr a n sp la n t( S ) U V M o d if y in g R is k V a ri a b le s R e p o rt e d R is k T y p e /D a ta F ST G o gi a et a l 2 0 1 3 R et ro sp ec ti ve C o h o rt U SA - C A 2 0 0 4 -2 0 0 8 5 5 6 3 1 7 c SC C K id n ey , h ea rt , lu n g, p an cr ea s, an d l iv er F ST I II II I IV V SC C H R ( 9 5 % C I) 3 .4 7 ( 1 .4 6 -8 .2 8 ) 2 .6 3 ( 1 .1 6 -5 .9 2 ) 2 .7 9 ( 1 .2 4 -6 .3 0 ) 2 .0 7 ( 0 .9 1 -4 .7 0 ) 1 .5 8 ( 0 .6 6 -3 .8 1 ) M o lo n ey e t  al 2 0 0 5 O b se rv at io n al co h o rt Ir el an d (2 0 0 0 -2 0 0 1 ) 2 7 0 4 4 S C C a n d 2 2  B C C K id n ey F ST % I II II I IV SC C 5 2 .3 % 2 5 .0 % 1 8 .2 % 4 .5 % B C C 5 4 .5 % 2 7 .3 % 1 8 .2 % 0 % D e R o sa e t  al 2 0 1 9 R et ro sp ec ti ve C o h o rt A u st ra li a 9 4 - H ea rt a n d l u n g F ST II I- V I I- II C ar ci n o m a ty p e - H R ( 9 5 % C I) N M SC - 0 .6 0 ( 0 .3 5 -1 .0 2 ) SC C - 0 .5 7 ( 0 .3 3 -1 .0 0 ) B C C - 0 .5 5 ( 0 .2 9 -1 .0 2 ) N M SC - 1 * SC C - 1 * B C C - 1 * N g et  a l  2 0 1 4 P ro sp ec ti ve co h o rt A u st ra li a (2 0 0 4 -2 0 0 9 ) 1 4 2 2 5 3 c SC C an d 8 8 B C K id n ey F ST I II II I IV C ar ci n o m a ty p e - ac cr u al ( SD ) N M SC - 2 .3 7 ( ± 3 .2 5 ) SC C - 1 .7 6 ( ± 2 .7 0 ) B C C - 0 .6 1 ( ± 1 .6 6 ) N M SC - 3 .0 5 ( ± 8 .8 8 ) SC C - 2 .4 1 ( ± 7 .4 8 ) B C C - 0 .6 4 ( ± 1 .6 0 ) N M SC - 0 .8 0 ( ± 1 .5 7 ) SC C - 0 .6 0 ( ± 1 .4 0 ) B C C - 0 .2 0 ( ± 0 .4 9 ) N M SC - 0 .4 5 ( ± 2 .8 5 ) SC C - 0 .4 0 ( ± 1 .7 5 ) B C C - 0 .0 5 ( ± 0 .1 6 ) T ab le 1 c o n ti n u es 4 Review | Dermatol Pract Concept. 2023;13(3):e2023065 K C R is k V a ri a b le S tu d ie d S tu d y A u th o r( S ) A n d Y e a r P u b li sh e d S tu d y D e si g n D a ta C o ll e ct io n Lo ca ti o n ( Y e a r R a n g e s) N u m b e r o f S u b je ct s in S tu d y K C R e p o rt e d Ty p e o f Tr a n sp la n t( S ) U V M o d if y in g R is k V a ri a b le s R e p o rt e d R is k T y p e /D a ta G ar ci a et a l 2 0 1 3 P ro sp ec ti ve + R et ro sp ec ti ve co h o rt M ed it er ra n ea n R eg io n (1 9 9 6 -2 0 1 0 ) 2 8 9 4 1 c SC C a n d 9 1 B C C K id n ey F ST I- II ≥ II I R el at iv e N M SC H R ( 9 5 % C I) 1 * 0 .5 ( 0 .2 7 -0 .9 2 ) D u cr o u x e t  al 2 0 1 4 R et ro sp ec ti ve co h o rt 1 9 9 6 -2 0 0 8 (F ra n ce ) 3 7 1 5 0 K C ( cS C C an d /o r B C C ) L u n g F ST I- II I IV -V I N M SC O R ( 9 5 % C I) 1 0 .9 1 ( 1 .4 5 -8 1 .7 7 ) 1 * C af o ri o e t  al 2 0 0 0 P ro sp ec ti ve C o h o rt It al y 3 0 0 5 3 S C C a n d 3 7 B C C H ea rt F ST II II I- IV N M SC H R ( 9 5 % C I) 2 .6 ( ± 1 -7 ) 1 * R ac e D u se n d an g et  a l 2 0 2 2 C as e- co n tr o l U SA - C A (2 0 0 9 -1 9 ) 3 3 0 8 O T R v s 6 5 ,8 8 3 n o O T R - H ea rt , k id n ey , li ve r, lu n g, a n d p an cr ea s R ac e W h it e A A A si an A m er ic an L at in x O th er cS C C H R ( 9 5 % C I) 1 .0 0 * 0 .0 4 ( 0 .0 2 -0 .0 7 ) 0 .0 7 ( 0 .0 5 -0 .0 9 ) 0 .2 3 ( 0 .1 8 -0 .2 9 ) 0 .5 2 ( 0 .4 1 -0 .6 5 ) A A = A fr ic an A m er ic an ; B C C = b as al c el l ca rc in o m a; C I = c o n fi d en ce i n te rv al ; cS C C = c u ta n eo u s sq u am o u s ce ll c ar ci n o m a; F ST = F it zp at ri ck s k in t yp e; H R = H az ar d R at io ; K C = k er at in o cy te c ar ci n o m a; N M SC = n o n -m el an o m a sk in c an ce r; O R = O d d s R at io ; SC C = s q u am o u s ce ll c ar ci n o m a; S D = s ta n d ar d d ev ia ti o n ; * = h az ar d o r o d d s ra ti o i n r ef er en ce t o t h is v al u e. Ta b le 1 . St u d ie s ex am in in g ke ra ti n o cy te c ar ci n o m a ri sk v ar ia b le s, F it zp at ri ck s k in t yp e, a n d r ac e in s o li d o rg an t ra n sp la n t re ci p ie n ts . ( co n ti n u ed ) Review | Dermatol Pract Concept. 2023;13(3):e2023065 5 Ta b le 2 . St u d ie s ex am in in g ke ra ti n o cy te c ar ci n o m a ri sk v ar ia b le s, s u n sc re en , a n d s u n e x p o su re i n s o li d o rg an t ra n sp la n t re ci p ie n ts . K C R is k V a ri a b le S tu d ie d S tu d y A u th o r( S ) a n d Y e a r P u b li sh e d S tu d y D e si g n D a ta C o ll e ct io n Lo ca ti o n ( Y e a r R a n g e s ) N u m b e r o f S u b je ct s In S tu d y K C R e p o rt e d Ty p e o f Tr a n sp la n t( S ) U V M o d if y in g R is k V a ri a b le s R e p o rt e d R is k T y p e /D a ta Su n sc re en Sa vo ia e t al 2 0 1 1 R et ro sp ec ti ve co h o rt It al y (1 9 9 7 -2 0 1 0 ) 2 8 2 9 9 S k in c an ce rs - 7 0 N M SC (4 7  B C C a n d 2 3  S C C ) K id n ey SS U se Y es N o R is k F ac to rs si gn ifi ca n t li n k N eo p la sm H R ( 9 5 % ) 1 .0 0 * 1 .2 5 ( 0 .5 6 -2 .7 9 ) N o s u n sc re en u se ( P = 0 .0 2 5 2 ) O u td o o r jo b ( P = 0 .0 4 1 3 ) U lr ic h e t al 2 0 0 9 C as e- co n tr o l B er li n , G er m an y 1 2 0 1 9 N M SC ( B C C an d S C C ) (8 SC C , 1 1 B C C ) H ea rt , k id n ey , an d l iv er t x ( 2 0 ea ch ) SS U se cS C C B C C P P < 0 .0 1 N o t si gn ifi ca n t Su n E x p o su re V ad n er k ar e t al 2 0 1 0 R et ro sp ec ti ve C o h o rt U SA - P it ts b u rg h , PA (2 0 0 3 -2 0 0 8 ) 5 4 3 1 7 S C C L u n g R is k f ac to r: R es id en ce i n re gi o n w it h h ig h su n e x p o su re SC C P v al u e P = 0 .0 0 0 1 C af o ri o e t al 2 0 0 0 P ro sp ec ti ve C o h o rt It al y 3 0 0 5 3 S C C a n d 3 7 B C C H ea rt R is k f ac to r: h ig h s u n li gh t ex p o su re SC C H R ( 9 5 % C I) 7 .6 ( 2 .5 -2 2 .8 ) P P = 0 .0 0 0 3 R o d ri gu ez -A co st a et a l 2 0 1 5 C as e- co n tr o l M ex ic o (2 0 1 1 -2 0 1 2 ) 1 4 0 5 9 S C C a n d 1 9 B C C K id n ey a n d li ve r R is k f ac to r: to ta l su n b u rd en (r ec re at io n al + o cc u p at io n al ) N M SC O R ( 9 5 % C I) ( P ) 1 9 ( 3 -1 2 0 ) (P < 0 .0 0 1 ) Ia n n ac o n e et a l 2 0 1 6 P ro sp ec ti ve C o h o rt Q u ee n sl an d , A u st ra li a (2 0 1 2 -2 0 1 4 ) 4 9 5 1 3 5 N M SC ( 4 1 cS C C , 5 0 B C C , 7 7 B o w en ) K id n ey a n d li ve r R is k f ac to r: B o rn i n A u st ra li a N M SC P R ( 9 5 % C I) 2 .3 8 ( 1 .2 8 -4 .4 2 ) H R = H az ar d R at io ; K C = k er at in o cy te c ar ci n o m a; N M SC = n o n -m el an o m a sk in c an ce r; O R = O d d s R at io ; P R = P re va le n ce R at io ; SS = S u n sc re en . 6 Review | Dermatol Pract Concept. 2023;13(3):e2023065 patients older than age 18 and collected one of the four UV modifying factors. These studies included solid organ transplants of the: kidney, heart, lung, liver, and pancreas. Dates for incorporated studies ranged from 2000 to 2022 (Figure 1). Results Thirteen studies were selected for review after assessing a total of 480 full-text studies. Overall, the 13 studies in- cluded 6910 patients with solid organ transplantations in Figure 1. Flowchart of the identification of eligible studies. Review | Dermatol Pract Concept. 2023;13(3):e2023065 7 NMSC incidence and found that higher tumor accrual rates in both FST I (1.76 SCC/patient per year, 0.61 BCC/patient per year) and FST II (2.41 SCC/patient per year, 0.64 BCC/ patient per year) compared to FSTs III, IV, and V [22]. A simi- lar association was reported in an Italian cohort study where FST II was found to be a significant risk factor (HR=2.60) in NMSC incidence in heart SOTR compared to FSTs III, IV, and V [23]. Although the Australian study noted both SCC and BCC, it is vital to point out the increased SCC:BCC ratio (2.86:1), an association comparable with previous studies [24,25]. Additionally, FST I patients specifically had a much higher SCC:BCC ratio compared to other FSTs. It is imper- ative for clinicians to keep this increased SCC:BCC ratio in mind when treating SOTR patients as this impacts the regu- larity of skin screenings and requires more patient-centered treatment plans. A retrospective and prospective follow-up study exam- ined the risk factors for NMSC in renal transplant patients. Lighter FSTs (I and II) were associated with a significantly greater risk of NMSC compared to FST ≥III (HR 0.50 +/- 0.27-0.92, P = 0.026) [26]. Interestingly, Garcia et al found an increased BCC:SCC ratio (2.21:1) which conflicts with the studies previously mentioned. This inverse relationship between lower FST and higher risk of NMSC in renal trans- plant patients was also supported by Savoia et al (BCC:SCC ratio 2.1:1) [27]. Lower FST has been shown in numerous studies to be a significant risk factor for incidence of NMSC, and more specifically, KC, in SOTR. Although previous studies have shown an overall increased SCC:BCC ratio, some studies have found a surprisingly increased BCC:SCC ratio. There is a need for additional well-designed prospective studies to be included in the literature to further distinguish the factors which affect varying SCC and BCC ratios. The Impact of Race on KC in SOTR Although race is associated with FST, many environmental, socioeconomic, genetic, and patient outcome factors con- tribute to race as a distinct identifier. Along with FST, race also contributes to SCC incidence in SOTR. A retrospective cohort study examining the incidence of SCC in SOTR from 2009 to 2019 found that the annual incidence rate of SCC in white SOTR was 4.70% compared to 0.38% in non-white SOTR (African American, Asian American, Latinx, Multiple/ Other, or Unknown) [28]. Additionally, white SOTR were more likely to have a history of skin cancers than non-white SOTR. This trend was consistent with Kang et al and could be the result of earlier diagnoses or a greater chance to get a diagnosis [28,29]. Latinx SOTR also had an increased SCC incidence compared to other non-white groups [28]. Our search was limited to one study that examined race associa- tion with KC incidence in SOTR. All 13 studies provide adequate data supporting in- creased risk for KC associated with one of the four UV mod- ifying risk factors. Seven studies explored FST impact and found that SOTR with lower FST (FST I and II) have an increased incidence of KC. One study identified the impact race has on KC incidence; the results indicated that white SOTR patients had a higher KC incidence than non-white SOTR. Within the non-white population, Latinx SOTR had the highest KC incidence. Two studies examined the impact of sunscreen application and suggested that controlled ap- plication of sunscreen can significantly reduce KC incidence in SOTR. Lastly, four studies explored sun exposure as a UV modifying factor and found that both occupational sun ex- posure and residence sun exposure are major contributors to KC incidence in SOTR. The Impact of FST on KC in SOTRs This systematic review explores the incidence of KC in adult solid organ transplant recipients of UV modifying risk fac- tors, including FST. Seven studies supported an increased risk in KC for lighter skin FSTs (FST I-II). A major cohort study by Gogia et. al examined 556 or- gan transplant recipients with skin cancer history between 2004 and 2008 and recorded patient demographics, trans- plant type, and FST [19]. SCC incidence and FST displayed an inverse relationship ie the risk of SCC increased with each incremental decrease in FST. FST I patients had a 1.67- fold increased risk in developing SCC compared to FST IV patients, but a FST I patients had an even higher, 3.47-fold risk increase when compared to FST VI patients [19]. This trend continued over a 15-year period where SCC incidence of FST I participants was 68% compared to 27% in FST VI participants. However, the 15-year SCC incidence rates for FST II and FST III participants were 66% and 63%, re- spectively, indicating that fair skin types were more likely to have to develop SCC than the overall population. This trend was observed in an earlier study examining skin cancer de- velopment in renal transplant recipients. Out of the 44 sub- jects that developed squamous cell carcinomas, 52.3% were of FST I while 25.0% were of FST II [20]. The remaining 22.7% were of FST III and FST IV. The results of this study were also suggestive that SCC were more probable to de- velop in lighter skin type individuals. Furthermore, an Aus- tralian retrospective cohort study that traced 94 heart and/or lung transplant patients reported results that also supported this trend. Compared to FSTs I-II, FSTs III-VI had a 0.57-fold decreased risk of developing SCC [21]. Although these stud- ies reiterated similar trends, some of the variability in SCC incidence can likely be attributed to the variability in world- wide sun exposure levels and various UV modifying factors. FST also impacts BCC incidence in SOTR. A 60-month prospective Australian study examined FST impact on 8 Review | Dermatol Pract Concept. 2023;13(3):e2023065 The Impact of Sun Exposure on KC in SOTR In addition to sun protective factors, sun exposure has been shown to be a major contributor to SCC in SOTR. For exam- ple, Queensland, Australia is known for its excessive sunlight exposure [33]. One study of SOTRs found that Australia SOTRs had a 10-year NMSC incidence of 70%, compared to SOTRs in Italy (10%) and Northern Europe (20%) [34]. Additionally, this study also found that cumulative amounts of sun exposure strongly predicted the risk of NMSC in both the Italian and Australian cohorts [34]. Moreover, the geo- graphic impact of Australia sun exposure on NMSC was supported by Iannacone et al. The authors reported that patients born in Australia had a 2.38 prevalence ratio for NMSC compared to those born outside of Australia [35]. A separate retrospective case-cohort study (1:3 case-to- control ratio) in Pittsburgh examined the impact of high- level sun exposure on SCC incidence in single and double lung OTR (N = 543). High-level sun exposure was defined as residence south of 35° latitude with high to very high UV indexes. The authors found that residing in high-level sun ex- posure areas was an independent risk factor for SCC in lung OTR (P = 0.0001) [36]. Additionally, 94% of the patients who developed SCC presented on sun-exposed parts of the body and this finding may be explained by the impact sun exposure has on the increased risk for SCC. In addition to residential sun exposure, Savoia et al retro- spective study reported that outdoor occupation was one of two exogenous risk factors significantly associated with skin can- cer incidence [27]. Additional studies have also reported sim- ilar conclusions regarding the association between increased outdoor labor and increased risk of skin cancer. A case-control study in Mexico displayed that greater than 20 hours per week of occupational sun exposure was a significant risk factor as- sociated with increased NMSC incidence (P < 0.01) [37]. An- other study examined the risk factors for skin cancers in heart transplant recipients and found that cumulative increased sun exposure during work was independently associated with an increased risk of SCC (P = 0.0003) [23]. Limitations This systematic review has several limitations. The first lim- itation is the high disparity in quantifiable variables to validly measure the effect of UV modifying factors reported in studies. Seven studies supported FST as a risk factor for skin cancer, but only one study supported race as a risk factor for cancer, even though both race and FST are factors determined by skin phe- notype. Therefore, we require more standardized protocols for SOTR studies that monitor KC to collect demographics such as race to further support its impact on increased KC incidence. Additionally, we were unable to account for the effect of time from SOTR status to KC presentation, and how this would be related to various UV modification habits in SOTR patients. Overall, white SOTR had a significantly higher incidence rate of SCC than non-white SOTR while the Latinx popula- tion had an increased SCC incidence when compared to the remaining non-white group. The Impact of Sun Protective Factors on KC in SOTR Sun protective factors, such as sunscreen, are major contrib- utors to SCC incidence in SOTR. In a 24-month prospec- tive case-control study of 120 patients, treatment groups were divided into a sunscreen group and a control group to explore the impact of regular application of >60 SPF sunscreen on SCC incidence in SOTR. The study included heart, kidney, and liver organ transplant recipients (OTR). After the 24-month phase, no new invasive SCC occurred in the sunscreen group while control patients developed 8 new invasive SCC (P < 0.01) (5 heart OTR, 3 kidney OTR, and 0 liver OTR) [30]. This trend was also supported by an Australian study of 1383 immunocompromised non-SOTR patients, demonstrating a similar trend found in both SOTR and non-SOTR populations [30,31]. Although the initial SOTR case-control study supported the potential protective benefits of sunscreen in decreasing the incidence of SCC, it is imperative to note that a 24-month period is too narrow to determine the full development of NMSC. Lastly, in a single-center retrospective study in Italy, Savoia et al examined risk factors for skin cancers in kid- ney OTR. They found that the two exogenous risk factors that were significantly associated with skin cancers were the lack of sunscreen use (P = 0.0252) and outdoor occupation (P = 0.0413) [27]. Although this controlled trial suggested that sunscreen is a protective factor against SCC in SOTR, a retrospective study examining NMSC incidence in kidney OTR found that self-reported sunscreen was not a signifi- cant protective factor in NMSC incidence [32]. This compar- ison highlights the importance of educating SOTR patients on daily appropriate usage of sunscreen and emphasizing the use of higher sunscreen strength to best achieve the potential reduced risks of the development of SCC. Overall, sunscreen may be an effective protective fac- tor to reduce the incidence of NMSC in SOTR. However, due to the limited number of supporting studies, we cannot draw conclusions regarding sunscreen potential protective benefits. Further studies are required to understand the as- sociation between sunscreen and NMSC development. Addi- tionally, although SPF was not a controlled variable, further research is required to determine the effect of varying SPF intensities in reducing NMSC incidence in SOTR. Future, prospective studies interested in this relationship should also explore determining an adequate cut-off point for SPF strength that is associated with a significantly decreased risk for NMSC. Review | Dermatol Pract Concept. 2023;13(3):e2023065 9 SOTR in comparison to kidney SOTR [39]. Gjersvik et al further confirmed this finding by displaying a 2.8-fold higher risk [40]. The increased risk can be explained by the elevated immunosuppressive dosage by heart SOTR compared to kidney SOTR [39]. Additionally, numerous studies have concluded that NMSC incidence increases in proportion to immunosuppressive duration [26,33,41,42]. We presented immunosuppressive drugs, percent distribu- tion of drug types, and median time of immunosuppres- sion for all included patients in Table 3. Lastly, although we analyzed the influence of exoge- nous factors on the development of NMSC, our review did not account for the impact of immunosuppression. Pharmacological immunosuppression is necessary for post-operative SOTR and is deemed the biggest risk factor contributing to NMSC incidence in SOTR [38]. NMSC incidence rates are proportional to the type of organ transplant, immunosuppressant type, dosage, and dura- tion of the drug [39]. A single-center Norwegian study found a 3-fold higher risk of developing SCC in heart Table 3. Immunosuppressive drugs, percent distribution of drug types, and median time of immunosuppression from studies included in retrospective analysis. Study Type of Immunosuppressant % of SOTR Median time Gogia et al 2013 NR NR NR Moloney et al 2005 Cyclosporine, Azathioprine, and Prednisolone NR NR De Rosa et al 2019 NR NR 8.4 years (range: 0.4-27 years) Dusendang et al 2022 Mycophenolate mofetil and Tacrolimus 93% 15 months Other Mycophenolate 53% 4 months Other Tacrolimus 44% 4 months Savoia et al 2011 Tacrolimus 58.9% 7.2 years Cyclosporine 36.2% Azathioprine, Mycophenolate, and Sodium mofetil NR Ng et al 2014 Calcineurin inhibitors (Cyclosporine or Tacrolimus), Mycophenolate mofetil, and Prednisolone 53% 11.6 years (+/- 8.2 years) Azathioprine, Mycophenolate mofetil, and Prednisolone 27% Garcia et al 2013 Mycophenolate, mTOR-Sirolimus, and/or Everolimus inhibitors 6.2% NR Tacrolimus and Mycophenolate 66.4% Cyclosporine and Mycophenolate 25.6% Older regimens and Azathioprine 1.7% Ducroux et al 2014 Cyclosporine 19.5% 8.2 years Tacrolimus 95.7% Sirolimus 20.8% Caforio et al 2000 Cyclosporin A and Azathioprine 79.3% NR Cyclosporin A, Azathioprine, and prednisone 20.7% Ulrich et al 2009 Cyclosporine, Prednisolone, and Mycophenolate or Azathioprine 33.3% 24 months Tacrolimus, Mycophenolate, and Prednisolone 33.3% Tacrolimus 33.3% Vadnerkar et al 2010 Calcineurin inhibitor, Mycophenolate, and Prednisolone 88.2% NR Voriconazole 23.5% 6 months Voriconazole 76.5% > 6 months Rodriguez-Acosta et al 2015 Cyclosporine, Azathioprine, and Prednisolone NR NR Iannacone et al 2016 Calcineurin inhibitor, Antiproliferative agent, and Corticosteroid 53.5% 8.9 years Calcineurin inhibitor with or without Corticosteroid 35.5% NR = not reported ; SOTR = solid organ transplant recipients. 10 Review | Dermatol Pract Concept. 2023;13(3):e2023065 9. Brenner M, Hearing VJ. The Protective Role of Melanin Against UV Damage in Human Skin†. Photochem Photobiol. 2008;84(3):539-549. DOI: 10.1111/j.1751-1097.2007.00226.x. PMID: 18435612. PMCID: PMC2671032. 10. Watson M, Holman DM, Maguire-Eisen M. Ultraviolet Radia- tion Exposure and Its Impact on Skin Cancer Risk. Semin Oncol Nurs. 2016;32(3):241-254. DOI: 10.1016/j.soncn.2016.05.005. PMID: 27539279. PMCID: PMC5036351. 11. Wu S, Han J, Vleugels RA, et al. Cumulative ultraviolet radiation flux in adulthood and risk of incident skin cancers in women. Br J Cancer. 2014;110(7):1855-1861. DOI:10.1038/bjc.2014.43. PMID: 24595003. PMCID: PMC3974077. 12. Xiang F, Lucas R, Hales S, Neale R. Incidence of nonmelanoma skin cancer in relation to ambient UV radiation in white populations, 1978-2012: empirical relationships. JAMA Dermatol. 2014; 150(10):1063-1071. DOI:10.1001/jamadermatol.2014.762. PMID: 25103031. 13. English DR, Armstrong BK, Kricker A, Winter MG, Heenan PJ, Randell PL. Case-control study of sun exposure and squamous cell carcinoma of the skin. Int J Cancer. 1998;77(3):347-353. DOI:10.1002/(sici)1097-0215(19980729) 77:3<347::aid-ijc7>3.0.co;2-o. PMID: 9663594. 14. Iannacone MR, Wang W, Stockwell HG, et al. Patterns and tim- ing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skin--a case-control study. BMC Can- cer. 2012;12:417. DOI:10.1186/1471-2407-12-417. PMID: 22994655. PMCID: PMC3517361. 15. Zanetti R, Rosso S, Martinez C, et al. The multicentre south European study “Helios”. I: Skin characteristics and sunburns in basal cell and squamous cell carcinomas of the skin. Br J Cancer. 1996;73(11):1440-1446. DOI:10.1038/bjc.1996.274. PMID: 8645595. PMCID: PMC2074488. 16. Gabros S, Nessel T, Zito P. Sunscreens And Photoprotection. StatPearls. Published online November 15, 2021. Available from https://www.ncbi.nlm.nih.gov/books/NBK537164/Accessed April 2, 2022. 17. van der Pols JC, Williams GM, Pandeya N, Logan V, Green AC. Prolonged Prevention of Squamous Cell Carcinoma of the Skin by Regular Sunscreen Use. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2546-2548. DOI:10.1158/1055-9965.EPI-06-0352. PMID: 17132769. 18. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. DOI:10.1136/bmj.n71. PMID: 33782057. PMCID: PMC8005924. 19. Gogia R, Binstock M, Hirose R, Boscardin WJ, Chren MM, Arron ST. Fitzpatrick skin phototype is an independent predictor of squamous cell carcinoma risk after solid organ transplanta- tion. J Am Acad Dermatol. 2013;68(4):585-591. DOI:10.1016/j .jaad.2012.09.030. PMID: 23107311. PMCID: PMC3562416. 20. Moloney FJ, Almarzouqi E, O’Kelly P, Conlon P, Murphy GM. Sunscreen use before and after transplantation and assessment of risk factors associated with skin cancer development in re- nal transplant recipients. Arch Dermatol. 2005;141(8):978-982. DOI:10.1001/archderm.141.8.978. PMID: 16103326. 21. De Rosa N, Paddon VL, Liu Z, Glanville AR, Parsi K. Nonmelanoma Skin Cancer Frequency and Risk Factors in Australian Heart and Lung Transplant Recipients. JAMA Dermatol. 2019;155(6):716. DOI:10.1001/jamadermatol.2018.4789. PMID: 30865218. PMCID: PMC6563540. Conclusions Overall, our systematic review of 13 retrospective cohort, prospective cohort, case-control, and observational studies suggests a significant association between UV modifying factors and the risk of KC among individuals who have un- dergone solid organ transplantation. The four UV modifying factors were FST, race, sunscreen use, and sun exposure. 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