Prevention and management of skin cancer in solid organ transplant recipients

INTRODUCTION — Solid organ transplant recipients are at increased risk for cutaneous malignancies (most commonly squamous cell carcinoma), a finding related to long-term immunosuppression. Because some skin cancers demonstrate aggressive biologic behavior in the setting of immunosuppression, care must be taken to identify and treat early lesions appropriately. In addition to treatments that directly target cutaneous malignancies, modulation of immunosuppression and preventive measures play an important role in the management of these patients. Organ transplant recipients with a history of skin cancer should be followed closely for the development of new lesions, locally recurrent lesions, and metastatic disease.

The prevention and management of skin cancers in organ transplant recipients will be reviewed here. The epidemiology and risk factors for skin cancers in organ transplant recipients, as well as a summary of other malignancies that develop with increased frequency after solid organ transplantation, are discussed separately. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients" and "Malignancy after solid organ transplantation".)

PRETRANSPLANTATION SCREENING — A dermatologic consultation is recommended before transplantation for the screening and treatment of skin cancer and precursor lesions. All suspicious lesions should be excised and sent for pathologic examination. Actinic keratoses, porokeratoses, and viral warts should be treated. A careful history of previous skin cancer should also be obtained to determine the appropriate follow-up frequency or the wait time before proceeding to transplantation [1,2].

Wait time — For patients with a history of prior cutaneous malignancy, the wait time before undergoing transplantation depends upon the tumor type and stage, presence or absence of high-risk features, and availability of a management approach alternative to transplantation. Consensus-based recommendations from the International Transplant Skin Cancer Collaborative are summarized here [2]:

●Transplant candidates with extensive field disease (ie, multiple actinic keratoses, disseminated porokeratosis) but without a history of skin cancer may proceed to transplantation, with the recommendations that all field disease be appropriately managed by the dermatologist.

●For patients with basal cell carcinoma or low-risk squamous cell carcinoma (SCC) that has been surgically excised with clear margins, no waiting time is required.

●For patients with a history of high-risk SCC (table 1) and for those with Merkel cell carcinoma stage IIa or less (local disease; any tumor size not invading bone, muscle, fascia, or cartilage; negative lymph nodes (table 2)), a two- to three-year waiting time is required.

●For patients with SCC and local nodal disease, a five-year wait time is considered prudent, following appropriate treatment with lymph node dissection and adjuvant radiation therapy.

●For transplant candidates with a history of melanoma in situ/lentigo maligna, no waiting period is required, but the patient should be followed up with regular skin exams.

●For renal transplant candidates with a history of stage Ia/Ib/IIa melanoma, a two- to five-year wait time is required before transplantation. A five-year delay is required for patients with stage IIb/IIc melanoma.

●Patients with distant metastatic diseases are not eligible for transplantation in most circumstances.

PREVENTION — Organ transplant recipients are approximately 65 to 250 times more likely to develop squamous cell carcinoma (SCC), which may be aggressive and associated with a much higher mortality rate than in the general population [3-5]. The preventive management of these patients requires a close collaboration between the dermatologist and transplant team and may involve:

●Patient education concerning sun protection and skin self-examination

●Choice and modulation of immunosuppressive therapy

●Chemoprevention

●Post-transplantation surveillance

Sun protection — Prior to and following transplantation, patients should be educated about the importance of sun protection and the recognition of the early signs of cutaneous malignancies. Sun avoidance and the regular use of sunscreens and sun-protective clothing is recommended [6].

The daily use of sun-protective measures may decrease the incidence of actinic keratoses and SCC in organ transplant recipients. In a nonrandomized controlled study of 120 transplant recipients, patients using daily sunscreen developed fewer actinic keratoses and SCCs than subjects with intermittent sunscreen use [7]. Despite the lack of high-quality evidence supporting the value of sun-protection measures for the prevention of post-transplant skin cancer, organ transplant recipients should be strongly encouraged to comply with sun-protective measures, including the use of daily sunscreen [8]. (See "Selection of sunscreen and sun-protective measures".)

Vitamin D deficiency is more likely to occur in patients who engage in strict sun protection. With approval of the patient's transplant team, vitamin D supplementation can be initiated in deficient patients [9].

Choice and modulation of immunosuppressive regimen — The choice of the immunosuppressive regimen may influence the risk of post-transplant skin cancer. Regimens including mammalian target of rapamycin (mTOR) inhibitors such as sirolimus and everolimus rather than calcineurin inhibitors may reduce the risk for skin cancer and prolong the time to onset [10].

mTOR inhibitors — Compared with calcineurin inhibitor-based regimens, immunosuppression with the mTOR inhibitors sirolimus or everolimus may reduce the risk for malignancies, including nonmelanoma skin cancer, in organ transplant recipients [10-19]:

●A 2014 meta-analysis of 21 randomized trials using individual data from 5876 kidney and kidney-pancreas transplant recipients who received immunosuppressive regimens either with or without sirolimus found that sirolimus was associated with a 40 percent reduction in the risk of malignancy and nonmelanoma skin cancer, compared with controls (adjusted hazard ratio [HR] 0.60, 95% CI 0.39-0.93) [20]. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus.

However, sirolimus was associated with an increased risk of death (HR 1.43, 95% CI 1.21-1.71). The increased mortality was driven by increased cardiovascular and infection-related deaths in the sirolimus group. An increased risk of all-cause mortality and death from malignancy associated with mTOR inhibitors (either sirolimus or everolimus) was also found in an observational study of 9353 kidney transplant recipients (HR 1.47, 95% CI 1.23-1.76 and HR 1.37, 95% 1.09-1.71, respectively) [21].

●In a 2015 meta-analysis including 39,039 kidney recipients, sirolimus was associated with a 51 percent reduction in the incidence of nonmelanoma skin cancer (incidence rate ratio [IRR] 0.49, 95% CI 0.32-0.76) [22]. This association was much stronger in trials comparing patients treated with sirolimus with those treated with cyclosporine (IRR 0.19, 95% CI 0.04-0.84), suggesting that the protective effect of sirolimus may be in part driven by the withholding of cyclosporine.

●In a five-year extension trial that compared sirolimus-based versus calcineurin inhibitor-based immunosuppression in kidney transplant recipients with one or multiple cutaneous squamous cell carcinomas (cSCCs), patients in the sirolimus group maintained a lower skin cancer rate over five years, with no difference in rejection or mortality between the two groups [23]. At five years, the rates of new skin cancers in the sirolimus group were significantly lower than those in the calcineurin inhibitor group (22 versus 59 percent for cSCC, 20 versus 37.5 percent for basal cell carcinoma [BCC], and 34 versus 66 percent for other skin cancers). The benefit was most marked in patients who converted to a sirolimus-based regimen after the development of the first cSCC (HR 0.20, 95% CI 0.07-0.57).

●In a retrospective study of kidney transplant recipients comparing everolimus with reduced calcineurin inhibitor versus sirolimus with mycophenolate mofetil, survival free of new nonmelanoma skin cancer was similar in the two treatment groups [24]. Nineteen patients (54 percent) in the calcineurin inhibitor with everolimus group and 22 patients (48 percent) in the sirolimus with mycophenolate mofetil group were diagnosed with at least one new nonmelanoma skin cancer.

Mycophenolate mofetil versus azathioprine — A few studies have shown that mycophenolate mofetil and mycophenolic acid are associated with a lower incidence of skin cancer in solid organ transplant recipients compared with azathioprine [25,26]. In a single-institution study including 544 patients who underwent lung transplantation (with a median survival of 11 years), the sequential use of azathioprine and mycophenolate mofetil (each for least one year) was associated with a lower risk of developing a cSCC compared with azathioprine use only (HR 0.24; 95% CI 0.10-0.56) [27].

Reduction of immunosuppressive therapy — Because increased intensity and duration of immunosuppression appear to promote the development of cutaneous malignancies in organ transplant recipients, reduction of immunosuppression may be considered in patients who develop numerous lesions, recurrent disease, or metastatic disease [28-33]. However, no randomized trials have evaluated the effect of reduction in immunosuppression on the development of multiple, recurrent, or aggressive SCC. A few observational studies suggest that reduction of immunosuppression may be of benefit:

●In a randomized trial of 231 renal transplant recipients, treatment with normal doses of cyclosporine and azathioprine versus low doses of these agents resulted in significantly fewer patients with squamous cell or basal cell cancers in the low-dose group (14.7 versus 22.6 percent) [30]. Low-dose therapy was associated with a higher rate of acute graft rejection (7.8 versus 0.9 percent), but graft survival rates were similar.

●In a series of six organ transplant recipients with a history of multiple post-transplantation SCCs, cessation of immunosuppressive therapy was associated with reductions in skin cancer development in four [31]. One patient who improved after cessation of immunosuppression had recurrence of new skin cancers after retransplantation and reinitiation of immunosuppressive therapy.

●In a retrospective study of nine renal transplant recipients with deeply invasive SCC and/or regional metastatic disease (involving adjacent soft tissues or lymph nodes), those patients in whom immunosuppression was reduced or discontinued had a significantly longer duration of survival free of distant metastatic disease compared with patients whose immunosuppression was unchanged [32].

Since reduction of immunosuppression can increase the risk for graft rejection, the risks and benefits of adjusting the level of immunosuppression must be carefully considered on an individual basis. Definitive guidelines have not been established. An expert consensus on the reduction of immunosuppression for specific skin cancer scenarios in organ transplant recipients has been published (table 3) [33]. (See "Malignancy after solid organ transplantation", section on 'Reduction in immunosuppression'.)

Chemoprevention for squamous cell carcinoma — Chemopreventive measures are considered for patients who develop multiple (more than five) SCCs per year, aggressive SCCs, or accelerated development of SCCs [34]. Medications and strategies that have been studied for the prevention of SCC in organ transplant recipients include acitretin, nicotinamide, capecitabine, and photodynamic therapy.

Acitretin — Systemic retinoids such as acitretin, isotretinoin, and etretinate (no longer commercially available) have been used for the prevention or reduction of nonmelanoma skin cancers [35-39]. Data from two randomized trials support the benefit of acitretin:

●In an open-label, randomized, crossover trial of 23 organ transplant recipients treated for 12 months with 25 mg/day of acitretin or a dose titrated according to patient tolerance, significantly fewer SCCs developed during acitretin therapy than during the treatment-free period [40]. A nonsignificant trend towards a reduction in BCC was also noted. Nine patients withdrew from the study due to drug-related side effects.

●In a six-month, randomized trial of 44 renal transplant patients treated with 30 mg/day of acitretin or placebo, significantly fewer skin cancers developed in patients treated with acitretin [41]. The majority of skin cancers detected (17 out of 20) were SCCs; new SCCs developed in 11 versus 47 percent of patients in the respective groups.

In contrast, a randomized dose-comparison trial in renal transplant recipients found no benefit of acitretin 0.2 or 0.4 mg/kg/day for three months followed by 0.2 mg/kg/day for nine months in the prevention of skin cancer [42]. Although actinic keratoses decreased by 50 percent with treatment in both groups, the numbers of new SCCs, BCCs, and keratoacanthomas were similar in the pretreatment and post-treatment periods. The majority of patients did not tolerate the dose of 0.4 mg/kg/day and required early dose reductions.

The major side effects of systemic retinoids include teratogenicity; dryness of the eyes, nose, lips, mouth, and skin (picture 1); abnormalities in liver function tests; and hyperlipidemia. Periodic laboratory monitoring is necessary. Since pregnancy must be avoided for three years after the discontinuation of acitretin, treatment usually is not given to women of childbearing potential. Contraception is required for only one month after the completion of isotretinoin; however, evidence for the efficacy of this agent for chemoprevention in organ transplant recipients is limited to a case report in which a patient improved with 0.5 mg/kg/day [43].

Acitretin should be started at low doses to facilitate tolerance of adverse effects [34]. We typically begin with 10 mg a day and gradually increase at one- to two-week intervals by increments dictated by patient tolerance of side effects. We treat most patients with a maintenance dose of 25 mg per day, but the final dose is individualized to balance clinical response with side effects. Acitretin is now available in multiple dose forms (10, 17.5, and 25 mg), which allows for a more individualized daily dose [34].

The effect of acitretin is limited to the duration of therapy; lesion development recurs rapidly after cessation of therapy [40,41]. Further studies are necessary to determine the long-term safety, efficacy, and optimal treatment regimen for acitretin as a chemopreventive agent in organ transplant recipients.

Nicotinamide — A randomized trial of oral nicotinamide 500 mg twice daily for 12 months in 386 immunocompetent participants with a history of two or more nonmelanoma skin cancers found a 20 percent reduction in the number of new BCCs and a 30 percent reduction in the number of new SCCs in the nicotinamide group, compared with the placebo group [44]. However, data on solid organ transplant recipients are limited to a few small, randomized trials and are inconsistent [45-47].

In the largest trial, 158 solid organ transplant recipients were randomized to oral nicotinamide 500 mg or placebo twice daily for 12 months [47]. During the intervention period, the mean number of keratinocyte cancers per participant was 2.6 in the nicotinamide group and 2.7 in the placebo group. The mean count of actinic keratoses over the trial period was 13.1 in the nicotinamide group and 12.8 in the placebo group.

Capecitabine — Treatment with capecitabine, an oral chemotherapeutic agent, may reduce the development of new cSCCs in solid organ transplant recipients. Following a report in which treatment with capecitabine halted the development of new cutaneous carcinomas and improved existing lesions in three transplant patients with histories of multiple SCCs [48], additional reports have suggested benefit [49,50]. In a case series in which 10 solid organ transplant recipients who had developed at least two nonmelanoma skin cancers within six months were treated with 21-day cycles of capecitabine (0.5 to 1.5 g/m² per day on days 1 to 14) for 5 to 24 months, 9 (90 percent) had reductions in the incidence of SCCs after beginning capecitabine [49]. Overall, the mean number of SCCs that developed per month decreased from 0.56±0.28 in the pretreatment period (generally 8 to 12 months) to 0.16±0.11 in the first year of the treatment period. Moderate to severe side effects led to dose alterations in seven patients, including two who eventually had to discontinue treatment. Additional studies are necessary to determine the efficacy and safety of capecitabine in this setting.

Photodynamic therapy — Studies assessing the efficacy and duration of effect of photodynamic therapy (PDT) for the prevention of SCC have yielded variable results [51-55]. In one split-site randomized trial involving 25 renal transplant recipients with clinically normal skin, patients received PDT at the start of the study and at six-month intervals for five years [55]. After three years of follow-up, actinic keratosis developed in 63 percent of untreated skin areas compared with 28 percent in PDT-treated skin, with a total number of 43 actinic keratoses in untreated skin versus 8 in treated skin. (See "Treatment of actinic keratosis", section on 'Photodynamic therapy'.)

Post-transplantation surveillance — Although a skin examination prior to transplantation is considered by many to be ideal, practical considerations often preclude this practice. A multidisciplinary, Delphi consensus recommended that all high-risk White patients be screened within two years after transplant and screening for White, Asian, Hispanic, and high-risk African American patients within five years after transplant. High risk was defined as heart or lung transplant, age greater than 50 years at time of transplantation, or male sex [56]. After the first examination before or after organ transplantation, patients should continue to have complete skin examinations on a regular basis. The frequency of visits depends upon the patient's risk factors and medical history. Definitive guidelines have not been established; we typically utilize the following follow-up schedule:

●No history of skin cancer or actinic keratosis – Once yearly for high-risk patients, less frequently for lower-risk patients

●History of actinic keratosis or one low-risk nonmelanoma skin cancer – Every six months

●Multiple nonmelanoma skin cancers or a history of a high-risk SCC – Every three months

●History of pretransplant melanoma or melanoma in situ – Every six months

●Post-transplant melanoma – Every three months for two years, then at least every six months

●Rapidly developing tumors, aggressive tumors, or metastatic skin cancer – Every four to six weeks

In all patients with a history of skin cancer, examination should include the palpation of lymph nodes.

In a Canadian population-based study including over 10,000 transplant recipients followed up for a median of 5.4 years, adherence to annual post-transplantation dermatologic examination for at least 75 percent of the follow-up time was associated with a 34 percent reduction in the rate of advanced nonmelanoma skin cancer compared with patients with less than 75 percent adherence, after adjusting for ethnicity and history of pretransplant actinic keratosis and skin cancers (HR 0.66, 95% CI 0.48-0.92) [57]. Of note, in this cohort only 45 percent of patients were ever seen by a dermatologist following transplantation and only 2 percent were fully adherent to annual skin examination during the entire post-transplant period.

Skin self-examination — Organ transplant recipients should be instructed to perform a skin self-examination on a monthly basis. The American Academy of Dermatology provides online information and tutorials on skin self-examination and early detection of skin cancer.

Several randomized trials and a systematic review support the efficacy of educational interventions using written materials, videos, or mobile device applications in promoting sun-protection behaviors among kidney transplant recipients [58-61]. However, none of these studies directly demonstrated the efficacy of such interventions in reducing the incidence of skin cancer after transplantation.

MANAGEMENT

Actinic keratosis — Actinic keratoses occasionally progress to cutaneous squamous cell carcinoma (cSCC), and the presence of multiple actinic keratoses on photodamaged skin can make it more difficult to detect early cSCCs (picture 2A-B). Thus, the treatment of these lesions is an important component of the management of organ transplant recipients. (See "Treatment of actinic keratosis".)

Local destructive therapies such as cryotherapy, electrocautery, curettage, or carbon dioxide laser can be used for the management of individual lesions. Field therapy with topical fluorouracil or imiquimod is an option for patients with numerous lesions. Initially, concerns over the induction of immune activation and subsequent organ rejection with topical imiquimod limited the use of this agent in the transplant population. However, the initial results of small, randomized trials suggesting that this agent can be used safely have been tempered by a single report of acute renal failure in a patient treated with imiquimod for viral warts to a surface area that may have exceeded that used to treat actinic keratosis [62]. In treating actinic keratosis, imiquimod is applied to limited areas (60 to 100 cm²) three times per week for up to 16 weeks [63,64]. The management of actinic keratosis is discussed in greater detail separately.

Photodynamic therapy (PDT) has also been used for the management of actinic keratosis, though the response to treatment in organ transplant recipients may be less favorable than in immunocompetent populations [65]. Several studies have investigated the role of interventions to augment PDT efficacy and reduce the pain associated with conventional PDT in this population [66-68]. In a small randomized trial, treatment of the involved areas with ablative fractional laser in combination with daylight PDT was more effective than daylight PDT or conventional PDT alone and better tolerated than conventional PDT [68].

Squamous cell carcinoma — cSCC is the most common cutaneous malignancy in solid organ transplant recipients [3,28,69,70]. As in the immunocompetent population, cSCC is most likely to occur in patients with lightly pigmented skin [70-72]. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients".)

In comparison with cSCC in immunocompetent patients, cSCC in organ transplant recipients is more likely to manifest as aggressive disease [73]. In an observational study, clinical and histopathologic factors associated with aggressive behavior of cSCC and basal cell carcinoma (BCC) were evaluated in 276 transplant recipients (153 with cSCC and 123 with BCC) and 277 immunocompetent patients (154 with cSCC and 123 with BCC) [74]. The cSCC recurrence rate was substantially higher among organ transplant recipients than immunocompetent patients (13 versus 2 percent). Moreover, histopathologic features associated with aggressive behavior, including deep tissue involvement, perineural invasion, and lymphatic invasion, were observed with significantly higher frequency among transplant recipients than among immunocompetent patients. In contrast, no difference in the clinical behavior of BCC was noted between the two groups.

The prognosis is poor for the 5 to 8 percent of patients who develop metastases (picture 3) [73,75]. In a retrospective study that included 58 organ transplant recipients with distant or systemic metastases of cSCC, the three-year disease-specific survival rate was 29 percent [73]. Thus, once detected, prompt, appropriate management of early squamous cell carcinoma (SCC) is essential [73,76].

Patient evaluation — All lesions that are suspicious for cSCC should be pathologically examined to confirm the diagnosis and to evaluate for features associated with aggressive disease (see 'Lesion classification' below). Biopsies of papular or nodular lesions should extend at least into the deep reticular dermis [77].

Patients who are determined to have cSCC should undergo a complete skin examination and palpation of draining lymph nodes. The need for additional laboratory or radiologic evaluation is based upon the detection of findings that suggest locoregional or metastatic spread of disease. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".)

Lesion classification — In immunocompetent patients, a combination of clinical and histopathologic features is used to classify individual SCCs as low risk or high risk for aggressive clinical behavior. These classifications are used to guide the approach to treatment.

In the 7^th edition American Joint Committee on Cancer (AJCC) staging system for cutaneous squamous skin cancer (table 4), tumors were classified as T2 or at higher risk if they were >2 cm in greatest dimension or any size with two or more high-risk features (ie, >4 mm depth, Clark level IV, perineural invasion, lymphovascular invasion, primary site on the ear or nonglabrous lip, and poorly differentiated histology) [78]. Immunosuppression was not included as a high-risk feature because traditionally clinical risk factors are not included in staging.

In September 2016, the AJCC and the Union for International Cancer Control (UICC) issued the 8^th Edition of staging guidelines [79]. The new guidelines came into general use in January 2018 and contain an updated cSCC staging system encompassing tumors located on the head and neck only, since the system was developed within the AJCC's head and neck committee. The new cSCC staging system has expanded the criteria for upstaging to T3 (table 5). (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Staging'.)

Although the prognostic value of the 7^th edition AJCC staging system for cSCC has been substantiated in a retrospective study including heart and lung transplant patients [80], a subsequent study suggests that the Brigham and Women's Hospital (BWH) alternative staging criteria (table 6) may better identify tumors in immunosuppressed patients with high potential for poor outcomes. However, in this relatively small study, the majority of lesions that had poor outcomes were either AJCC 7^th edition T1/T2 or BWH T1/T2a [81]. Studies evaluating the prognostic value of the 8^th edition of the AJCC staging system in transplant recipients are eagerly awaited.

Further modifications to the AJCC staging system have been proposed with the aim of a more accurate stratification of prognostic groups [82,83]. Additional high-risk clinical and histologic features of cSCC that may be considered when selecting treatment include [84]:

●Location in the "mask areas" of face (central face, eyelids, eyebrows, periorbital, nose, lips, chin, mandible, preauricular and postauricular skin/sulci, temple, ear), genitalia, hands, and feet

●Large size – ≥10 mm on scalp, forehead, cheeks, neck or pretibial area; ≥20 mm on trunk or extremities

●Indistinct borders

●Rapid growth

●Recurrent lesion

●Lesion in site of chronic inflammation or prior radiation therapy

●Presence of neurologic symptoms

●Histology:

•Poorly differentiated

•Acantholytic (adenoid), adenosquamous, desmoplastic, or metaplastic (carcinosarcomatous) histopathologic subtypes

•Perineural, lymphatic, or vascular involvement

Treatment — Based upon multiple population-based studies indicating an increased likelihood for aggressive disease in organ transplant recipients, invasive cSCCs in this group of patients are generally considered high-risk lesions [3,77,85-87]. Thus, procedures that provide pathologic confirmation of complete tumor removal, such as Mohs surgery or conventional surgical excision with margin control, are the preferred treatments for invasive SCCs in these patients to prevent local recurrence and disease spread. Lesions classified as high-risk cSCC by AJCC criteria or alternative staging systems may require additional work-up (eg, computed tomography [CT] or magnetic resonance imaging [MRI], sentinel lymph node biopsy) and/or adjunctive therapy.

Squamous cell carcinoma in situ (Bowen's disease) — Options for the treatment of cSCC in situ are similar to those in immunocompetent patients. Frequently employed therapies include surgical excision, electrodesiccation and curettage (ED&C), and topical chemotherapy [88]. The results of small randomized trials suggest that imiquimod, a topical immunomodulating agent, can be used safely in organ transplant recipients when applied to limited areas (60 to 100 cm²) [63,64]. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)", section on 'Bowen's disease (squamous cell carcinoma in situ)'.)

Invasive lesions without additional high-risk features — Common treatments for cSCCs in organ transplant recipients that lack other features of aggressive disease (eg, small, well-differentiated lesions in low-risk sites) include surgical excision and ED&C. Destructive treatments such as ED&C do not provide pathologic confirmation of lesion removal and are primarily reserved for SCC in situ or carefully selected invasive lesions that lack additional high-risk features.

Surgical excision — cSCCs without additional high-risk features are frequently managed with conventional surgical excision. Lesions should be excised with a margin of tissue that extends 4 to 6 mm beyond the peripheral edge of erythema, and the specimen should be sent for postoperative pathologic margin assessment. Mohs surgery, a tissue-preserving, specialized surgical procedure that is used to evaluate 100 percent of the tissue margins, is generally not necessary. However, Mohs surgery may be appropriate in cases where tissue conservation is desired. (See "Mohs surgery".)

Electrodesiccation and curettage — ED&C, a procedure that involves three cycles of scraping of the tumor with a curette followed by electrodesiccation, is an alternative treatment for lower risk lesions. The efficacy of ED&C for cSCC in organ transplant recipients is supported by the results of a retrospective study of 211 cSCCs in 48 patients [89]. After a mean follow-up period of 50 months, residual or recurrent cSCC occurred in only 6 percent. The procedure often results in a depressed, hypopigmented oval scar and is generally reserved for lesions in noncosmetically sensitive sites, such as the trunk and extremities (excluding hands and feet). (See "Minor dermatologic procedures", section on 'Curettage and electrodesiccation' and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)", section on 'Curettage and electrodesiccation'.)

Advantages of ED&C are that the procedure is quick, generally well tolerated, and less expensive than excisional surgery. The rapid nature of the procedure can facilitate the treatment of patients who repetitively develop new lesions.

The main disadvantage of ED&C is the lack of histologic margin control, which underlies the importance of carefully selecting lesions for treatment. ED&C should generally not be performed in hair-bearing areas because the presence of terminal hair follicles may reduce the efficacy of the procedure. In addition, ED&C cannot reliably eradicate lesions that extend into the subcutaneous fat. If fat is reached early during the curettage stage, ED&C should be abandoned, and the tumor should be removed surgically.

Some clinicians choose to perform ED&C at the time of biopsy on lesions that are clinically consistent with small, well-differentiated cSCCs. If pathology results demonstrate aggressive histopathologic features, subsequent surgical excision should be performed to ensure adequate tumor removal.

All sites treated with ED&C should be followed closely for lesion recurrence. We typically follow such patients at three- to six-month intervals.

Cryosurgery — Cryosurgery is infrequently used for the management of low-risk cSCC in immunocompetent patients because of the difficulty in obtaining the requisite temperatures for tumor destruction in a uniform manner and the significant tissue edema and drainage that follow the procedure. In addition, recurrent disease is sometimes difficult to detect in the resulting scar. Although we typically do not use cryosurgery for the treatment of cSCC in organ transplant recipients, practitioners with extensive experience in its use for skin malignancies may find it useful. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)", section on 'Cryotherapy'.)

Invasive lesions with additional high-risk features — cSCCs in immunosuppressed patients that demonstrate other high-risk features (eg, large size, poor differentiation, high-risk site) should be managed with techniques that provide pathologic confirmation of tumor removal. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

Mohs surgery is our preferred treatment for cSCCs in such patients. Mohs surgery is a tissue-sparing surgical technique that provides evaluation of 100 percent of the margins of excised tissue. (See "Mohs surgery".)

Although reported cure rates for Mohs surgery for cSCC exceed those for other treatment modalities (five-year cure rates of greater than 96 percent) [90,91], there have been no randomized trials comparing the efficacy of Mohs surgery with other therapies for cSCC. One retrospective study that evaluated the efficacy of Mohs surgery for 260 high-risk cSCCs in 215 patients (20 percent of whom were immunosuppressed) found local recurrences of only three lesions (1.2 percent) at a mean follow-up of 3.9 years [92]. Six tumors metastasized (2.3 percent), resulting in one fatality.

Unfortunately, Mohs surgery is time consuming and not universally available. If Mohs surgery cannot be performed, surgical excision with intraoperative frozen sections may be used to remove aggressive lesions. If neither technique is available and tissue conservation is not a concern, conventional surgical excision with postoperative margin examination may be used. Lesions treated with conventional surgical excision should be excised with at least 6 to 10 mm margins beyond the edge of erythema [76]. Guidelines from the National Comprehensive Cancer Network state that lesions ≥20 mm on the trunk or extremities should be excised with 10 mm margins [77].

As in immunocompetent patients, the role of sentinel lymph node biopsy for cSCC in organ transplant recipients remains uncertain. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma", section on 'Sentinel lymph node biopsy'.)

Indications for radiation therapy — Radiation can be used to treat cSCCs in patients who are unable to tolerate surgery. Radiation also is used as an adjunctive therapy for lesions that cannot be completely excised or that demonstrate extensive perineural involvement, especially nerves of larger diameter [76]. A disadvantage of radiation therapy is a possible increased risk for the future development of skin cancer in treated sites [93] and possible increased difficulty in treating recurrences. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Radiation therapy' and "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Ionizing radiation' and "Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma", section on 'Ionizing radiation'.)

Severe or metastatic disease — The management of organ transplant patients with life-threatening, metastatic disease is challenging. Metastatic disease has responded to systemic therapies such as platinum-based chemotherapeutic agents, capecitabine [48], and cetuximab [94,95]. Fatal diffuse alveolar damage has been reported in two lung transplant patients treated with cetuximab for metastatic cSCC, which raises concern about its use in such patients [96].

Treatment with immune checkpoint inhibitors in transplant recipients with advanced cancers may improve the outcomes but is associated with a high risk of rejection [97,98] (see "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Cutaneous squamous cell carcinoma'):

●In a pooled analysis that included 64 transplant recipients with various metastatic cancers, disease control rates varied, from 35 percent with ipilimumab, 37 percent with nivolumab, and 53 percent with pembrolizumab [97]. Unfortunately, organ rejection occurred in a substantial number of patients, ranging from 54 percent with nivolumab, 39 percent with pembrolizumab, and 23 percent with ipilimumab.

●In a multicenter, retrospective study of 69 kidney transplant recipients receiving immune checkpoint inhibitors for advanced cSCC (n = 24) or melanoma (n = 22), the response rate was 36 percent in the cSCC group and 40 percent in the melanoma group [98]. Twenty-nine patients (42 percent) developed acute rejection in a median time of 24 days since immune checkpoint inhibitor initiation, and 19 patients lost their allograft.

Basal cell carcinoma — Basal cell carcinoma (BCC) is not associated with the same level of morbidity and mortality as SCC in organ transplant recipients. The management of BCC in this population resembles management in the immunocompetent patients. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence".)

Imiquimod is a topical immunostimulatory agent that is sometimes used for the treatment of superficial BCC. The use of imiquimod for limited periods on small areas (60 to 100 cm²) appears to be safe in organ transplant recipients [63,64]. (See 'Actinic keratosis' above and "Treatment and prognosis of basal cell carcinoma at low risk of recurrence", section on 'Imiquimod'.)

Melanoma — The management of melanoma in organ transplant recipients usually parallels the care of melanoma in the general population [99]. Patients with early-stage melanoma frequently can be managed with surgical excision; sentinel lymph node biopsy is indicated for lesions >1 mm in depth. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

The use of systemic immunomodulatory or molecularly targeted therapies for metastatic melanoma has not been specifically studied in the organ transplant population. Immunostimulatory therapies such as interferon are generally considered unfavorable due to the possibility of graft rejection [100]. (See "Interleukin 2 and experimental immunotherapy approaches for advanced melanoma" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

The use of immune checkpoint inhibitors for metastatic melanoma treatment in solid organ transplant recipients is controversial due to minimal data to guide care. Case reports suggest ipilimumab may be more tolerated than programmed cell death protein 1 (PD1) inhibition in these patients, but further study is needed. Graft rejection has been documented with both medications [101-103]. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

Immunosuppression reduction — The appropriate management of immunosuppression in patients diagnosed with melanoma has not been definitively determined; however, in general, immunosuppression should be reduced to the minimal regimen necessary to maintain organ tolerance (table 3). Greater reduction in immunosuppression can be considered in advanced cases, if the benefits of doing so are perceived to exceed the risks associated with rejection of the transplanted organ.

Immunosuppression with sirolimus has been associated with a reduced risk of malignancy in organ transplant recipients [11,104]. However, the specific impact of sirolimus in patients who develop melanoma after organ transplantation is unknown.

Kaposi sarcoma — Reducing the level of immunosuppression is the primary therapy for Kaposi sarcoma in organ transplant recipients (table 3) [29,105]. In addition, regression of Kaposi sarcoma has been reported in renal transplant patients after a change in immunosuppressive medication from cyclosporine to sirolimus [106-109]. Local and systemic therapies may also be used in the management of these patients. (See 'mTOR inhibitors' above and "Malignancy after solid organ transplantation", section on 'Kaposi sarcoma'.)

Merkel cell carcinoma — No specific guidelines exist for the management of Merkel cell carcinoma in organ transplant recipients [110,111]. Surgical excision is the usual treatment of choice with radiation as an adjuvant therapy in some cases [110]. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma".)

Reductions in immunosuppressive regimens have been reported to lead to temporary and partial regression of Merkel cell carcinoma in a few patients (table 3) [112,113]; however, additional studies are necessary to determine the best approach to treatment in organ transplant recipients.

FOLLOW-UP — Solid organ transplant recipients who have been treated for skin cancer should have complete skin examinations on a regular basis. The palpation of lymph nodes should be performed at each visit. The frequency of visits depends upon the patient's medical history and the type and clinical behavior of the tumor. (See 'Post-transplantation surveillance' above.)

PROGNOSIS — A cohort study including nearly 500,000 patients who received a solid organ transplantation in the United States between 1987 and 2013 examined the all-cause and skin cancer-specific mortality [114]. After a median follow-up time of 4.5 years (range 1.8 to 8.3 years), the skin cancer (squamous cell carcinoma, melanoma, and Merkel cell carcinoma) specific mortality was approximately 35 per 100,000 person-years, a rate nearly nine times higher than that reported for the general population [115]. Of interest, skin cancer-specific mortality was higher than breast cancer- and colon cancer-specific mortality (11.52 and 23.53 per 100,000 person-years, respectively). White patients in the 5- to 10-year post-transplantation period had the highest risk (hazard ratio 6.29, 95% CI 4.63-8.53). Other factors significantly associated with the risk of death from skin cancer included male sex, age >50, and thoracic transplantation.

Although limited prognostic data are available on patients who develop melanoma following organ transplantation, the results of a few studies suggest that while organ transplant recipients with thin melanomas may have survival rates that are comparable to patients in the general population, those with thicker lesions may have worse prognoses [99,116,117]. The largest study is a retrospective review of records from 638 patients with 724 post-transplantation melanomas that compared three-year survival rates in this population with survival data on melanoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program [116]. Melanoma-specific survival rates were lower than expected among organ transplant recipients with melanomas with 1.5 to 3.0 mm Breslow thickness but not significantly different from SEER data for lesions <1.5 mm. Moreover, a separate retrospective review that included 91 post-transplantation melanomas found that although disease outcomes were comparable to the general population for T1 or T2 tumors (≤2 mm thick), the prognosis was significantly worse for T3 or T4 tumors (>2 mm thick) [117]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

Data on the prognosis of patients with melanoma prior to organ transplantation also are limited [99,116,118]. An analysis of the data from two retrospective studies [117,119] with a total of 17 patients who had invasive melanoma prior to organ transplantation (median depth 1 mm, range 0.35 mm to 18 mm) found no disease recurrences or disease-related deaths after organ transplantation within a median follow-up period of 5.5 years [120]. Of note, the majority of patients were transplanted more than two years after treatment of their melanomas. In contrast, recurrences of pretransplant melanoma were reported in 6 out of 31 patients in another retrospective study [118]. The six patients died 6 to 30 months after transplantation.

Merkel cell carcinoma in transplant recipients tends to have a more aggressive course than in immunocompetent patients; approximately 70 percent of patients develop lymph node involvement, and the mortality rate at two years is estimated to be 56 percent [111]. Therefore, patients should be followed closely for the development of metastatic disease. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'Prognosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer".)

SUMMARY AND RECOMMENDATIONS

●Pretransplantation screening – Chronic immunosuppression in organ transplant recipients is associated with a high risk for cutaneous malignancies. Early detection and treatment of skin cancers, modulation of immunosuppression, and preventive measures play an important role in the management of these patients. A dermatologic consultation is recommended before transplantation for the screening and treatment of skin cancer and precursor lesions. A careful history of previous skin cancer should be obtained to determine whether a wait time is needed before proceeding to transplantation. (See 'Pretransplantation screening' above and 'Wait time' above.)

●Preventive measures – The preventive management of skin cancer in organ transplant recipients requires a close collaboration between dermatologists and transplant teams and involves patient education, choice and modulation of the immunosuppressive regimen, and post-transplantation surveillance (see 'Prevention' above):

•Sun protection – Transplant recipients should be counseled on sun avoidance, the use of sunscreens and sun-protective clothing, and the warning signs of cutaneous malignancy. Patients should be instructed to perform a skin self-examination on a monthly basis. (See 'Sun protection' above.)

•Modulation of immunosuppressive regimens – Because type, intensity, and duration of immunosuppression appear to promote the development of cutaneous malignancies in organ transplant recipients, modification or reduction of immunosuppression may be beneficial for patients who develop numerous lesions, recurrent disease, or metastatic disease (table 3). (See 'Choice and modulation of immunosuppressive regimen' above.)

•Chemoprevention – Chemoprevention with acitretin may be of benefit in patients who develop multiple or aggressive squamous cell carcinomas (SCCs). (See 'Chemoprevention for squamous cell carcinoma' above.)

●Post-transplantation surveillance – After transplantation, patients should continue to have total body skin examinations on a regular basis. We typically perform full skin examinations at least once yearly on individuals with lightly pigmented skin. More frequent examinations are indicated in patients with a history of actinic keratoses or skin cancer. Daily sun protection should be strongly encouraged. (See 'Post-transplantation surveillance' above.)

●Management of cutaneous squamous cell carcinoma – All lesions suspicious for cutaneous squamous cell carcinoma (cSCC) in organ transplant patients should be biopsied and sent for pathologic evaluation. Patients should be staged based on the American Joint Committee on Cancer 8^th edition criteria (table 5) and the alternative Brigham and Women's Hospital staging scheme (table 6). The treatment of SCCs is based upon the presence or absence of high-risk features (see 'Squamous cell carcinoma' above):

•Invasive cutaneous squamous cell carcinoma without additional high-risk features – Because cSCCs in organ transplant recipients are generally considered high-risk lesions, excisional therapies that provide evaluation of histologic margins are generally preferred. Some clinicians perform electrodesiccation and curettage at the time of biopsy on lesions that are clinically consistent with small, well-differentiated cSCCs. If pathology results demonstrate aggressive histopathologic features, subsequent surgical excision should be performed to ensure adequate tumor removal. (See 'Invasive lesions without additional high-risk features' above.)

•Invasive cutaneous squamous cell carcinoma with additional high-risk features – For cSCCs in organ transplant recipients that exhibit additional high-risk features (eg, large size, poor differentiation, high-risk site), we suggest treatment with Mohs surgery due to the high cure rates and tissue-sparing effect of this treatment (Grade 2B). If Mohs surgery is not available, excision with intraoperative frozen sections can be utilized. If neither of these options is feasible, patients can be managed with conventional surgical excision with postoperative margin assessment. (See 'Invasive lesions with additional high-risk features' above.)

●Management of other skin cancers – Basal cell carcinoma (BCC), melanoma, and Merkel cell carcinoma are managed similarly in organ transplant recipients and immunocompetent patients. Modulation of immunosuppression is the primary treatment for Kaposi sarcoma in organ transplant recipients. There are no definitive guidelines regarding alteration in immunosuppressive regimens in patients with BCC, melanoma, or Merkel cell carcinoma. The risks and benefits of reduction in immunosuppression should be considered carefully. (See 'Basal cell carcinoma' above and 'Melanoma' above and 'Kaposi sarcoma' above and 'Merkel cell carcinoma' above.)

●Prognosis – Population-based data on skin cancer mortality among organ transplant recipients are limited. A cohort study including nearly 500,000 patients who received a solid organ transplantation in the Unites States estimated a mortality from all skin cancers, including SCC, melanoma, and Merkel cell carcinoma, of approximately 35 per 100,000 person-years, a rate nearly nine times higher than that reported for the general population. (See 'Prognosis' above.)