Version May 2024
INTRODUCTION — The long-term immunosuppressive therapy required to maintain host tolerance of a transplanted organ contributes to an increased risk for malignancy in organ transplant recipients. Skin is the most common site for the development of malignancy; in particular, cutaneous squamous cell carcinomas (cSCCs) and basal cell carcinomas (BCCs) are frequently detected [1,2]. A variety of factors, including the intensity and duration of immunosuppression, patient ethnic background, patient sun exposure history, and geographic location, can influence the likelihood for the development of skin cancer in these patients.
The most common skin cancers that develop in solid organ transplant recipients will be reviewed here. The management of skin cancer in solid organ transplant recipients and information on other malignancies in organ transplant recipients are discussed elsewhere. (See "Prevention and management of skin cancer in solid organ transplant recipients" and "Malignancy after solid organ transplantation" and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)
INCIDENCE
Adult transplant recipients — Skin cancers account for almost 40 percent of malignancies in organ transplant recipients and develop in more than 50 percent of White organ transplant recipients [3,4] and in approximately 6 percent of non-White patients [5,6]. In the latter group, approximately two-thirds of the skin cancers occur on partially sun-exposed or sun-protected areas (eg, genitals) [6]. The most commonly reported skin cancers in this population include cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), melanoma, and Kaposi sarcoma [3,7-9].
In a large cohort of 10,649 adult transplant recipients from the United States Transplant Skin Cancer Network who received a primary transplant in 2003 and were followed up for a median time of six years, 861 patients (8 percent) developed a post-transplant skin cancer (812 cSCCs, 75 melanomas, and 2 Merkel cell carcinomas) [10]. The estimated overall incidence rate was 1437 per 100,000 person-years. Predictors of post-transplant skin cancer included pretransplant skin cancer (hazard ratio [HR] 4.69, 95% CI 3.26-6.73), male sex (HR 1.61, 95% CI 1.34-1.89), thoracic organ transplant (HR 1.51, 95% CI 1.26-1.82), White race (HR 9.04, 95% CI 6.20-13.18), and age at transplantation ≥50 years (HR 2.65, 95% CI 2.12-3.21).
In a Canadian cohort of 10,198 transplant recipients, 1690 (16.6 percent) developed a keratinocyte carcinoma (BCC or invasive cSCC) after a median of 3.96 years (range 1.94 to 7.09) post-transplant, with an incidence rate of 2.63 per 100 patient-years (95% CI 2.51-2.76) [11]. The age-, sex-, and calendar year-adjusted standardized incidence ratio (SIR) was nearly sevenfold higher than that in the general population (SIR 6.61, 95% CI 6.31-6.93). Age, White race, pretransplant skin cancer, post-transplant precancerous skin lesions, and male sex were strong predictors of post-transplant skin cancer. Pretransplant skin cancer, and in particular nonmelanoma skin cancer (NMSC), may also be a risk factor for post-transplant malignancies other than skin cancer. In a large cohort of adult kidney recipients transplanted between 2005 and 2013 including 1671 recipients with and 102,961 recipients without pretransplant skin malignancy, the risk of post-transplant solid tumors was higher among patients with pretransplant NMSC compared with patients without pretransplant NMSC (HR 1.55, 95% CI 1.05-2.30) [12]. Patients with pretransplant skin cancer also had an increased risk of graft failure and death.
A trend toward a reduced incidence of cSCC and BCC in the last two decades has been noted in an Irish nationwide study of 3580 solid organ transplant recipients followed up for a median time of seven years (SIR 26.4 [95% CI 21.5-32.4] and 9.1 [95% CI 7.4-11.3] in 1994 to 1996, and 6.3 [95% CI 2.3-16.7] and 3.2 [95% CI 1.4-7.1] in 2012 to 2014, respectively) [13].
Pediatric transplant recipients — cSCC, BCC, melanoma, and Kaposi sarcoma account for 13 to 55 percent of all post-transplantation malignancies in children [14]. In a cohort of 1734 children (median age 14 years) from the Australian and New Zealand Dialysis and Transplant Registry, 196 (11 percent) developed an NMSC over a median follow-up period of 13.4 years [15].
PATHOGENESIS — Although the pathways that lead to an elevated risk for cutaneous malignancy in organ transplant recipients are not fully understood, it is generally accepted that immunosuppressive medications used to induce tolerance to the donor organ play an important role. Proposed mechanisms through which immunosuppression may contribute to the development of skin cancer include [16]:
●Reduced immune surveillance, thereby facilitating the survival and proliferation of atypical cells.
●Direct or contributory carcinogenic effects of immunosuppressive agents, such as azathioprine or cyclosporine [17]. Calcineurin inhibitors have been shown to impair cell ability to repair ultraviolet radiation-induced DNA damage via decreased transcription of xeroderma pigmentosum complementation groups A and G genes XPA and XPG, two components of the nucleotide excision repair system [18]. (See 'Role of specific immunosuppressants' below.)
●Proliferation of oncogenic viruses in the setting of immunosuppression. Epstein-Barr virus (EBV), human papillomavirus (HPV), Kaposi sarcoma herpes virus (KSHV), human T cell lymphotropic virus type 1 (HTLV-1), and Merkel cell polyomavirus (MCPyV) are the main viruses associated with the development of cancer in immunosuppressed patients. (See 'Squamous cell and basal cell carcinoma' below and 'Kaposi sarcoma' below.)
●A systematic review of tumor profiling studies of cutaneous squamous cell carcinoma (cSCC) found that mutations in the genes coding for the glutathione S-transferase family of proteins and the gene coding for IRF4 may play a role in regulating the risk for keratinocyte carcinoma in transplant recipients [19].
The impact of immunosuppression on skin cancer development is supported by the results of a French series of 181 immunosuppressed renal transplant patients that included 15 patients with cutaneous malignancies. In this study, patients who developed skin cancer had significantly lower mean CD4 cell counts than patients without skin cancer (330/mm3 versus 503/mm3) [20].
SQUAMOUS CELL AND BASAL CELL CARCINOMA — Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) account for more than 90 percent of cutaneous malignancies in organ transplant recipients [3,21,22].
Clinical presentation — As in immunocompetent patients, cSCC typically presents as a scaly, erythematous papule, nodule, or plaque within an area of actinic damage (picture 1A-C). In some organ transplant recipients, particularly fair-skinned individuals with histories of extensive sun exposure, areas such as the back of the hand or balding scalp may develop numerous cSCCs and actinic keratoses (picture 2). Lip cancer can also be seen with increased frequency among solid organ transplant recipients [23]. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)
In organ transplant recipients, cSCC may be painful [24]. The sensation of pain associated with a cSCC is thought to be a warning signal for invasive tumor [25] and has been associated with an increased risk of overall mortality in these patients [26].
Like cSCC, BCC mimics its appearance in the general population, typically manifesting as pearly papules with or without ulceration or erythematous macules or patches in photoexposed areas (picture 3A-F). (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis" and "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation'.)
Epidemiology — In contrast to the general population, in which the incidence of BCC exceeds that of cSCC, most estimates of the ratio of cSCC to BCC in organ transplant recipients range from 1.5:1 to 5:1 [4,21,27-30]. Some authors have reported much higher ratios; in one retrospective study of 312 heart transplant recipients in the United States, out of 1395 skin cancers that developed in the study population over the course of 2097 person-years, 1236 (89 percent) were cSCCs and 151 (11 percent) were BCCs, with a ratio of cSCC to BCC of 8:1 [31].
Compared with the general population, organ transplant recipients are approximately 65 to 250 times more likely to develop cSCC and 6 to 16 times more likely to develop BCC [4,7,32].
In a Swedish, population-based study including 10,476 recipients transplanted from 1970 to 2008, 668 patients were diagnosed with 2231 cSCCs. Compared with the general population, transplant recipients were over 100 times more likely to develop an cSCC (standardized incidence ratio [SIR] 121, 95% CI 116-127) [33]. The risk was highest among heart and/or lung recipients.
In an Australian study of 361 organ transplant recipients with Fitzpatrick skin types I to IV (table 1), the incidence of new skin cancers rose as the time from transplantation increased. Among patients who had been immunosuppressed for less than 5, 5.1 to 10, 10.1 to 20, or more than 20.1 years, 29, 52, 72, and 82 percent, respectively, had developed at least one nonmelanoma skin cancer (NMSC) after organ transplantation [28].
Although cSCC and BCC are considered the most common skin cancers in organ transplant recipients, it must be noted that these carcinomas are much less common in non-White transplant recipients than in White transplant recipients [9,34-36]. In a retrospective study of 542 renal transplant patients in South Africa followed for a mean of 6.3 years, cSCC or BCC developed in 10 out of 185 White patients and none of the non-White patients [34]. In a retrospective review of non-White organ transplant recipients, African American patients had an increased incidence of human papillomavirus (HPV)-related cSCC in the groin and genitalia [37].
Rates of cSCC and BCC were also low in a cohort study of 4444 Korean organ transplant recipients; 15 years after organ transplantation, the cumulative incidences of cSCC, cSCC in situ, BCC, Kaposi sarcoma, and all primary skin cancers were 0.88, 0.81, 0.25, 0.28, and 2.31 percent, respectively [36]. Although the likelihood of skin cancer was low among organ transplant recipients, the risk for these cancers greatly exceeded the risk in the general population. As an example, after the fifth post-transplantation year, the risk for invasive cSCC among organ transplant recipients was more than 60-fold greater than the risk for invasive cSCC in the general Korean population.
Risk factors
Ultraviolet radiation, skin phenotype, and geographic location — Ultraviolet radiation [1,3,29,38-42] and fair phenotypic features (Fitzpatrick types I to III with light-colored hair and eyes) are known risk factors for the development of cSCC and BCC in the general population and also increase the risk for cSCC or BCC in organ transplant recipients [29,40,43-46]. However, NMSCs also occur in non-White transplant recipients; in these patients, tumors are more often located in non-sun-exposed areas and are, in most cases, associated with HPV infection [37]. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors" and "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis" and "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)
The incidence of skin cancer in organ transplant recipients varies geographically. Estimates of NMSC incidence after organ transplantation in the United States and Western Europe have ranged from 5 percent at 2 years, 10 to 27 percent at 10 years, and 40 to 60 percent after 20 years [21]. However, the rates of NMSC are higher in Australia, a finding that is likely related to greater solar exposure in a predominantly fair-skinned population. Between 70 and 82 percent of organ transplant recipients in Australia are diagnosed with NMSC within 20 years after transplantation [21].
Pre- and post-transplant history of skin cancer — In a series of 361 renal transplant recipients in Australia, a history of either cSCC or BCC prior to organ transplantation significantly increased risk for the development of cSCC or BCC after transplantation [40]. The presence of more than 100 actinic keratoses prior to organ transplantation was also strongly associated with the occurrence of skin cancer. In another study including over 104,000 kidney transplant recipients, patients with a history of pretransplant skin cancer (n = 1671) had a nearly threefold increased risk of post-transplant malignancies, including cSCC, BCC, lymphoproliferative disorders, and solid tumors, compared with patients without pretransplant skin cancer [12]. In the same study, pretransplant skin cancer was also associated with a 20 percent increase in overall mortality.
Many patients who develop one cSCC or BCC after organ transplantation will develop additional lesions [31,43,47]. In a retrospective study of 239 renal transplant recipients with cSCC or BCC in the Netherlands, the cumulative incidence of new skin cancer after the development of an initial lesion was 32 percent after one year, 59 percent after three years, and 72 percent after five years [43]. A separate retrospective study of cardiac transplant patients in the United States found cumulative incidence rates of a second cSCC at the same time points of 44, 67, and 76 percent, respectively [31]. The cumulative incidence rates for a second BCC were 32, 49, and 51 percent, respectively.
Type of transplant — The results of some observational studies have suggested that the risk for NMSC is greater in lung, heart, or pancreas-kidney transplant recipients than in kidney transplant patients [48-50] and is lowest in liver transplant recipients [36,51,52].
●In a single-institution study of 166 lung and heart-lung transplant recipients, 47 patients (28 percent) developed 211 skin cancers after a median follow-up of three years [50]. At 5 and 10 years post-transplantation, the cumulative incidence was 31 and 47 percent, respectively, significantly higher than that observed in heart and pancreas transplant recipients.
●In a series of 94 Australian heart and lung transplant recipients, 57 (61 percent) developed 801 NMSCs after a median of 8.4 years following transplantation [53].
●In a cohort study of 2561 heart transplant recipients and renal transplant recipients in Norway, heart transplant recipients were 2.9 times more likely to develop cSCC than renal transplant patients (95% CI 1.3-6.2) after adjustment for age at transplantation and immunosuppressive regimen [48].
●In contrast, a French cohort study that included 121 renal transplant patients and 67 heart transplant patients followed for up to five years found that among patients who had developed one post-transplant squamous cell carcinoma (SCC), greater numbers of subsequent nonmelanoma skin tumors (cSCCs, BCCs, Bowen's disease, premalignant keratoses, and keratoacanthomas) developed in the renal transplant patients (mean number of tumors 9.7 versus 4.6) [44].
Intensity, type, and duration of immunosuppressive therapy — The results of several studies suggest that the degree and duration of immunosuppression influence the risk for NMSC, particularly SCC. (See 'Role of specific immunosuppressants' below.)
●In a retrospective cohort study of 262 renal transplant recipients in the United Kingdom that compared treatment with a three-drug regimen (cyclosporine, azathioprine, and prednisolone) with a two-drug regimen (azathioprine and prednisolone), patients treated with the three-drug regimen had a significantly greater incidence of SCC [35]. The difference in BCC incidence between the two groups was not significant.
●A systematic review and meta-analysis of 27 studies found an increased risk of SCC, but not BCC, in organ transplant recipients treated with azathioprine compared with those treated with other immunosuppressive regimens (pooled relative risk 1.56, 95% CI 1.11-2.18) [54]. Azathioprine has also been associated with an increased risk of melanoma [55] and Merkel cell carcinoma [56].
●In an uncontrolled, prospective study of 300 heart transplant recipients in Italy (mean follow-up 4.6 years), patients who exhibited greater signs of organ rejection, which would have required treatment with higher levels of immunosuppression, had a significantly higher rate of SCC [29]. A subsequent nonrandomized, prospective study in 230 heart transplant patients from the same institution found that the risk for SCC (but not BCC) three years after transplantation correlated with the overall level of immunosuppression, rather than with a specific immunosuppressive drug [42].
History of transplant rejection may increase the risk of cSCC. In a single-institution study including 1648 renal transplant recipients, of whom 126 (7.5 percent) had experienced an episode of rejection, the incidence of cSCC was higher in the rejection group (8.7 versus 2.2 percent); moreover, patients in the rejection group developed a cSCC earlier than those in the no-rejection group (median lag time 2.5 versus 4.2 years) [57].
Role of specific immunosuppressants — Although a role of immunosuppression as an inciting factor for the development of skin cancer in organ transplant recipients is generally accepted, the impact of specific immunosuppressive agents remains unclear. Although the overall level of immunosuppression appears to be an important factor in the development of skin cancers [1,16,21,29,58-60], the contribution of individual immunosuppressive agents may not be equivalent (table 2).
Cyclosporine and azathioprine — Treatment with cyclosporine or azathioprine has been linked to the development of skin cancer in multiple clinical studies [39,43,48,61-64], and the results of laboratory studies have suggested that these agents may also influence the development of skin cancer through nonimmunologic pathways. Mutagenic effects have been observed following cellular exposure to the combination of ultraviolet light and azathioprine [65-69], and changes in cell morphology and inhibition of DNA repair, apoptosis, and p53 function have been associated with exposure to cyclosporine [16,70-72]. Additional studies are necessary to determine the clinical relevance of these observations.
Data from two observational studies suggest that immunosuppression with mycophenolate mofetil may be associated with lower risk for skin malignancy compared with azathioprine-based regimens [61,73].
mTOR inhibitors (sirolimus and everolimus) — Evidence suggests that sirolimus, compared with other immunosuppressive agents, is associated with a lower risk for skin malignancies in solid organ transplant recipients [74-78].
●A 2014 meta-analysis using individual patient data from 5876 kidney and kidney-pancreas transplant recipients from 21 randomized trials evaluated the risk of malignancy and death associated with immunosuppressive regimens with and without sirolimus [77]. Compared with controls, sirolimus was associated with a 56 percent decrease in the risk of NMSC (hazard ratio [HR] 0.44, 95% CI 0.30-0.63). This result was most striking among patients who converted to sirolimus from another immunosuppressive regimen (HR 0.32, 95% CI 0.24-0.42).
●A subsequent single-institution study evaluated the risk of a second post-transplant skin cancer among recipients of various organ transplants who were or were not converted to sirolimus after a first post-transplant cancer of any type [78]. The risk of skin cancer was significantly lower in the sirolimus group compared with the non-sirolimus group (27 versus 38 percent). Multivariate analysis showed that independent predictors of skin cancer after a first post-transplant cancer were a pretransplant history of skin cancer (subhazard ratio [SHR] 2.1, 95% CI 1.2-3.7), having had a skin cancer as first post-transplant cancer (SHR 5.5, 95% CI 2.5-6.4), and treatment with sirolimus (SHR 0.6, 95% CI 0.4-0.9).
●A study including 45,000 kidney transplant recipients from the United States Renal Data System (USRDS) examined the risks of complications at three years after transplantation associated with different early immunosuppressive regimens [79]. Compared with standard maintenance regimen (tacrolimus, mycophenolate, and prednisone), a sirolimus-based regimen was associated with a significant reduction in the risk of NMSC (HR 0.71, 95% CI 0.60-0.84) but increased risk of infectious complications, graft failure, and death.
●An analysis of data on 95 kidney transplant recipients from the Australian and New Zealand Dialysis and Transplant Registry previously included in a randomized trial comparing everolimus with reduced cyclosporine with mycophenolate sodium and standard cyclosporine for post-transplant maintenance immunosuppression found that everolimus with reduced exposure to cyclosporine was associated with a substantial reduction in the risk of NMSC, nonskin cancers, and any cancers (HR 0.34, 95% CI 0.13-0.91; HR 0.35, 95% CI 0.09-1.25; and HR 0.32, 95% CI 0.15-0.71, respectively) [80].
However, a 10-year, single-institution study including 3539 solid organ transplantation recipients did not confirm these findings [81]. In this study, the incidence of cSCC was not reduced among the 488 patients with ever use of sirolimus, compared with those who were not exposed to sirolimus (adjusted HR 1.18, 95% CI 0.84-1.16).
●(See "Malignancy after solid organ transplantation", section on 'Immunosuppression'.)
●(See "Malignancy after solid organ transplantation", section on 'Immunosuppression'.)
Age at transplantation and genetic factors — Older age at transplantation may increase the likelihood of NMSC and may be associated with development of lesions earlier in the post-transplant period [4,10,11,29,39,42]. In a population-based study of renal transplant recipients in Ireland, the incidence for NMSCs peaked at approximately six years after transplantation in patients older than 50 years compared with 10 to 12 years post-transplantation in younger patients [7]. Of note, the increase in risk was extraordinarily high for the young transplant patients compared with an age-matched, nontransplanted population; the risk for skin cancer was 200 times greater for these patients.
A common polymorphism in the folate pathway has been associated with an increased risk of cSCC in transplant patients. In a cohort of 367 renal transplant patients, those who carried the polymorphism MTHFR:C677T had a statistically significant increase in risk for cSCC (odds ratio [OR] = 2.54) compared with those who did not have the polymorphism [82]. More studies are necessary to explore the role of MTHFR:C677T in the development of cSCC.
Particular forms of DNA damage in immunosuppressed organ transplant recipients may contribute to increased risk for cSCC or aggressive tumor behavior [83,84]. In one study, a significant reduction in allelic balance in the D9S162 locus on chromosome 9p21-22 was detected in cSCCs from immunosuppressed organ transplant recipients compared with cSCCs from immunocompetent patients [83]. Further study is necessary to determine the etiology and clinical relevance of this finding.
HPV infection — The role of human papillomavirus (HPV) in the development of cSCC remains uncertain. HPV has been detected at a greater frequency in lesional versus nonlesional skin in organ transplant recipients with SCC (90 versus 11 to 32 percent of specimens positive for HPV) [85]. Beta-HPV subtypes, such as HPV 5, HPV 8, and HPV 9 (which are considered to be nonpathogenic to the general population), can induce preneoplastic and neoplastic skin lesions in immunocompromised patients and may play a causal role in post-transplant cSCCs [86,87]. High beta-HPV viral load in eyebrow hairs is associated with a greater risk of SCC in organ transplant recipients [88]. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Human papillomavirus infection'.)
Voriconazole — Voriconazole, a second-generation triazole broad-spectrum antifungal medication commonly used after lung transplantation, is associated with increased cutaneous photosensitivity and has been linked with the development of aggressive SCCs in immunocompromised patients [89]. In a single-institution, retrospective study including 455 lung transplant recipients seen over a 20-year period, voriconazole exposure was associated with a 73 percent increased risk of developing SCC (HR 1.73, 95% CI 1.04-2.88) [90]. The risk increased by 3 percent with each additional 30-day exposure (HR 1.03, 95% CI 1.02-1.04).
Risk of second malignancy — An analysis of data from the United States Scientific Registry of Transplant Recipients and cancer registries from 15 states, including nearly 120,000 White organ transplant recipients, found that cSCC, but not BCC, was associated with an increased risk of developing second malignancies (HR 1.44, 95% CI 1.31-1.59) [91]. cSCC was also associated with increased risk of HPV-related cancers, including anal cancer (HR 2.77, 95% CI 1.29-5.96) and female genital cancers (HR 3.43, 95% CI 1.44-8.19).
MELANOMA
Incidence — Organ transplantation is associated with an increased risk of melanoma. A 2015 meta-analysis of 20 cohort studies found that the pooled risk of melanoma was 2.71 (95% CI 2.23-3.30), with considerable heterogeneity among studies [92]. The largest published investigation, a United States population-based study of 139,991 transplant recipients followed for a median period of four years, identified 519 patients with invasive melanoma and 190 with in situ melanoma (incidence rates 74 and 27.1 per 100,000 person-years, respectively) [55]. Incidence increased sharply in the first four years after transplantation before declining steadily. The risk of invasive melanoma was more than twofold higher than in the general population (standardized incidence ratio [SIR] 2.20, 95% CI 2.01-2.39). The greatest increase was noted for regional stage melanoma (SIR 4.11, 95% CI 3.27-5.09) and for melanomas on the head and neck (SIR 3.34, 95% CI 2.85-3.90). The risk was higher in renal transplant recipients than in liver and lung recipients. Other factors associated with increased risk included male sex, increasing age, and azathioprine maintenance therapy [55].
These findings have been confirmed in an analysis of data from a cohort of over 105,000 renal transplant recipients from the United States Renal Data System (USRDS) database (years 2004 through 2012) [93]. The prevalence of melanoma in this cohort was 0.5 percent, with an SIR of 4.9 compared with the Surveillance, Epidemiology, and End Results (SEER) population. Male sex, increasing age, and treatment with cyclosporine or sirolimus were associated with increased risk of melanoma.
The risk of melanoma among African American transplant patients is also increased greatly. In a cohort of 89,786 renal transplant recipients, the annual incidence of melanoma was 17 times greater in African American transplant recipients than in the African American general population (13.3 per 100,000 population versus 0.8 per 100,000 population) [94].
As with nonmelanoma skin cancer, the intensity and duration of immunosuppression may be an important determinant of melanoma risk in organ transplant recipients [95]. Transmission of melanoma from organ donors to organ recipients has also been reported. In a review of 104 donor-transmitted cancer cases, melanoma was the second most frequent transmitted cancer (17 percent) after renal cancer [96]. (See "Malignancy after solid organ transplantation", section on 'Donor transmission'.)
Mortality — Melanoma-specific mortality is higher in transplant recipients than in nontransplanted patients and is among the highest, compared with other cancers, even when stage and treatment are taken into account [55,97-99].
●In a United States, cohort study, the mortality was threefold higher in transplant recipients compared with nonrecipients (hazard ratio [HR] 2.98, 95% CI 2.26-3.93) [55].
●A Swedish, population-based study comparing the melanoma-specific mortality among patients with post-transplantation melanomas with patients with melanoma in the general population provided a similar estimate (HR 3.0, 95% CI 1.75-5.3) [98].
●In a Canadian, population-based study, melanoma-specific mortality was nearly twofold higher in transplant recipients than in the nontransplant population, independent of stage (adjusted HR 1.93, 95% CI 1.03-3.63) [99].
KAPOSI SARCOMA — Kaposi sarcoma (KS) is a tumor of endothelial cell origin associated with herpes human virus-8 (HHV-8) infection that occurs with increased frequency in the setting of immunosuppression [1,7]. Most cases of organ transplant-related KS have occurred in individuals of Mediterranean, Jewish, Arabic, Caribbean, or African descent [3,8]. In a South African cohort study, KS was the most common cancer detected in non-White renal transplant recipients [8]. In the United States, among 244,964 transplant recipients from 1987 to 2014, 163 (0.07 percent) developed KS [100]. Males, non-White patients, and lung transplant recipients were at increased risk of KS.
KS often develops relatively quickly after organ transplantation; the mean interval to diagnosis is 13 months [3]. Men are more likely to be affected than women. The clinical manifestations typically resemble those of classic KS. Approximately 90 percent of patients develop cutaneous and/or mucosal lesions, and lesions on the lower extremities are common (picture 4A-C). Visceral involvement develops in 25 to 30 percent of renal transplant recipients and 50 percent of heart or liver transplant recipients [3]. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment" and "AIDS-related Kaposi sarcoma: Staging and treatment".)
MERKEL CELL CARCINOMA — Merkel cell carcinoma (MCC) is a rare tumor of neuroendocrine origin that usually presents as a red or red-blue papule or nodule in a sun-exposed area (picture 5A-C). (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)
●Incidence – The incidence of MCC is greatly increased among solid organ transplant recipients [56,101,102]. In a large population-based study of nearly 200,000 solid organ transplant recipients, the MCC risk was 24-fold higher than in the general population (standardized incidence ratio [SIR] 23.8, 95% CI 19.6-28.7), with the highest incidence occurring 10 or more years after transplant [56]. The incidence of MCC appears to increase with age at the time of transplant, with over 70 percent of cases occurring in patients who were older than 50 years at the transplant, and with time since transplant, with the highest incidence observed 10 years or more after transplant.
●Risk factors – Immunosuppressive regimens may influence the occurrence of MCC. Induction with monoclonal antibodies and maintenance immunosuppression with tacrolimus or mycophenolate mofetil seem to be associated with a lower incidence of MCC; in contrast, incidence is highest in patients treated with a combination of cyclosporine and azathioprine [56]. Merkel cell polyomavirus (MCPyV) infection has been linked to the development of MCC [103]. However, the role of MCPyV in the development of MCC in solid organ transplant recipients is uncertain. Compared with MCC occurring in immunocompetent patients, MCPyV is less frequently detected in MCC in transplant recipients [104]. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Merkel cell polyomavirus'.)
●Mortality – Based on small case series, solid organ transplant recipients have a 3- to 12-fold increased risk for MCC-specific death compared with immunocompetent patients [104,105].
OTHER CUTANEOUS CANCERS — Other skin cancers reported in solid organ transplant recipients include sebaceous carcinoma, appendageal cancers [106,107], cutaneous T and B cell lymphomas [108-110], angiosarcoma [111-113], malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma), atypical fibroxanthoma [114], leiomyosarcoma [115], and natural killer cell lymphoma [116]. However, data are lacking regarding the incidence and outcome of these neoplasms in this population.
SUMMARY AND RECOMMENDATIONS
●Incidence and risk factors – Organ transplant recipients require chronic immunosuppression, which contributes to an increased risk for skin cancer. More than 50 percent of White organ transplant recipients develop at least one cutaneous malignancy. Reduced immune surveillance, direct carcinogenic effect of immunosuppressive agents, and proliferation of oncogenic viruses in the setting of immunosuppression may contribute to the development of skin cancer. (See 'Incidence' above.)
●Nonmelanoma skin cancers – Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) account for the majority of skin cancers in organ transplant recipients. Multiple factors (including patient-specific characteristics; type of transplant; intensity, type, and duration of immunosuppression; geographic location; and sun exposure) influence the risk for the development of these lesions. In non-White transplant recipients, tumors are more often located in non-sun-exposed areas and are, in most cases, associated with human papillomavirus infection. (See 'Squamous cell and basal cell carcinoma' above and 'Risk factors' above.)
●Melanoma – Organ transplant recipients are also at increased risk of developing an invasive melanoma. The risk of death from melanoma is threefold higher in transplant recipients compared with nonrecipients. (See 'Melanoma' above.)
●Clinical presentation – The appearance of skin cancer lesions in organ transplant recipients generally resembles lesions in immunocompetent patients, but organ transplant recipients are more likely to develop multiple tumors and aggressive tumors (picture 2). cSCC, BCC, melanoma, and Merkel cell carcinoma frequently develop on sun-exposed areas. The lower legs are a common site of involvement in Kaposi sarcoma. (See 'Squamous cell and basal cell carcinoma' above and 'Melanoma' above and 'Kaposi sarcoma' above and 'Merkel cell carcinoma' above.)
●Role of specific immunosuppressant agents – The impact of specific immunosuppressants on the development of skin cancer is unclear. Tumor development seems to be most related to the intensity and duration of immunosuppression. Compared with other immunosuppressive regimens, immunosuppression with mTOR inhibitors may reduce the risk for nonmelanoma skin cancer in organ transplant recipients. (See 'Role of specific immunosuppressants' above and "Prevention and management of skin cancer in solid organ transplant recipients", section on 'mTOR inhibitors'.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
