Skin cancers and other cutaneous diseases in renal transplant recipients: a single Italian center observational study

ARTICLE

ejd.2011.1272

Auteur(s) : Paola SAVOIA¹ paola.savoia@unito.it, Elena STROPPIANA¹, Giovanni CAVALIERE¹, Simona OSELLA-ABATE¹, Elisabetta MEZZA², Giuseppe Paolo SEGOLONI², Maria Grazia BERNENGO¹

¹ Division of Clinics and Oncological Dermatology, University of Turin, via Cherasco 23, Turin, Italy

² Division of Nephrology Dialysis and Transplantation, San Giovanni Battista Hospital and University of Turin, Turin, Italy

Reprints: P. SAVOIA

Cutaneous involvement is frequent in chronic renal failure, due to the complementary functions of skin and kidney in excretion and idro-electrolytic homoeostasis [1]. It is reported that 50-100% of patients with end-stage renal insufficiency have at least one non-specific or specific skin disease [1]; the majority of these dermatological disorders disappear after kidney transplantation [2]. However, infectious diseases [3], pre-malignant actinic keratoses (AKs) and cutaneous cancers [4] occur frequently in organ transplant recipients, as consequence of the long-term immunosuppressive treatment [5]. In particular, the relative risk of developing cutaneous malignancies is 20 to 40 fold increased, in comparison with the general population [5, 6].

In this study, a dermatological screening was performed to evaluate the incidence of cutaneous tumours and other skin diseases in a group of 282 kidney transplant recipients. The impact of long-term immunosuppressive therapy and the relative effects of single agents on the development of cutaneous malignancies were assessed, as were the roles of endogenous and exogenous risk factors, with the aim of giving specific clinical surveillance recommendations.

Materials and methods

Patients

We collected the data of 282 renal transplant recipients; dermatological consultations were performed between April 1997 and March 2010 after a median time since transplantation of 7.2 years (range 0.1-36.1). During the first visit, after obtaining informed consent, we collected the most important clinical information about the patient's history. In particular, gender, age at transplantation and type and duration of immunosuppression were recorded. Endogenous–skin type, freckles, family history of skin cancer, seborrhoeic keratoses (SKs)–and exogenous risk factors–outdoor/indoor job, use of sunscreen, frequency of sun exposure, use of UV lamps, past sun burns and solar lentigines–were also considered. We also documented the presence of AKs and any excision of skin cancers carried out before or after kidney transplantation. A complete dermatological visit was performed, to identify any dermatological disease or relevant skin lesions. All suspicious neoformations were excised and histologically analyzed.

The influence of immunosuppressive therapy was also pointed out: we investigated the role of single class agents or combination regimens, focusing on eventual differences between cyclosporine and other drugs. The immunosuppressive regimen in our population consisted of combinations of systemic corticosteroids, azathioprine, cyclosporine, tacrolimus, mycophenolate and sodium mofetil and mTOR inhibitors in the majority of cases.

Statistical analysis

Differences between patients with and without skin cancer were analysed by the chi-square test for categorical variables. Multivariate logistic regression was performed to evaluate the influence of significant parameters on skin cancer development. The age distribution and the time of immunosuppression were expressed as median, minimum and maximum; the Mann-Whitney test was used to analyse the differences. Kaplan-Meier analyses were used to estimate the cumulative incidence of skin cancer after transplantation; as opening dates we used the date of transplantation; as closing dates we used the dates of first skin cancer diagnosis, patients’ death or last follow-up. Skin cancers diagnosed before transplantation were not considered [7, 8].

Results

Patients

Patients’ clinical characteristics are summarized in table 1 table 1. Our population consisted of 282 KTRs: 173 males (61.3%) and 109 females (38.7%). Transplantations were performed from 1974 to 2009; 229 of 282 (81.2%) were transplanted after 1995. Median age at transplantation was 50 years, both for males and females. Median age at dermatological consultation was 60 years for males and 56 years for females. Median duration of immunosuppression was 7.2 years and was significantly higher in males (p = 0.0054).

Table 1 Clinical characteristics of patients.

Cutaneous diseases

Table 2 summarizes the cutaneous disorders diagnosed in KTRs at the time of the dermatological consultation. Infectious diseases were the most frequent dermatological disorders (16.7%). Viral warts were identified in 29 subjects (10.3%), other cutaneous infections in 18 (6.4%). Cutaneous inflammatory diseases developed in 42 patients (14.9%); whereas autoimmune diseases involving the skin were rare and affected only 5 patients.

Table 2 Dermatological diseases observed in renal transplant recipients.

^a 6 herpes zoster, 4 erysipelas, 3 onychomycosis, 1 tinea cruris, 1 herpes simplex labialis, 1 ulcerative cutaneous tubercolosis, 1 molluscum contagiosum, 1 genital candidiasis.

^b 10 seborrhoeic dermatitis, 6 prurigo nodularis, 4 lichen simplex chronicus, 3 eczema, 1 Zoon's balanitis, and 1 chondrodermatitis.

^c 2 alopecia areata, 2 lichen ruber planus and 1 vitiligo.

Thirty patients (10.6%) experienced cutaneous side effects from immunosuppressive drugs. We observed 2 cases of rapamycin-related oral aphthosis, 1 everolimus-related urticaria and 1 idiopathic maculopapular rash. The majority of cutaneous side effects (26/30) were noted in patients who were receiving corticosteroids, and especially in males (p = 0.0372).

Skin cancers

Medical history revealed a skin cancer removed before transplantation in 8 of our 282 patients. Four patients had a previous diagnosis of basal cell carcinoma (BCC), 1 of BCC and squamous cell carcinoma (SCC), 2 of melanoma and 1 of keratoacanthoma. Three of these patients experienced another skin cancer after transplantation, whereas the other 5 were disease-free at the last dermatological visit. Data analysis identified 99 of 282 KTRs (35.1%) who developed skin cancers after renal transplantation: in particular 70 out of 99 (70.7%) developed NMSCs (47 BCC, 21 SCC, 1 patient with concomitant BCC/SCC, 1 patient with both SCC and sarcoma). The BCC/SCC ratio was 2.1. About 54% BCCs and 81% SCCs developed on sun-exposed areas. The remaining 29 patients were diagnosed with 11 melanomas, 11 Kaposi's sarcomas and the other 7, various skin cancers (table 3 table 3).

Table 3 Skin tumors observed in renal transplant recipients.

^a (1 high malignancy cutaneous B cell lymphoma, 1 Merkel cell carcinoma, 1 liposarcoma, 2 high malignancy epithelioid angiosarcoma, 1 giant cell carcinoma, 1 malignant pilomatricoma).

After a median follow-up of 7.9 years, 14 of the 99 patients with a previous cutaneous tumour had another skin cancer removed. Subsequent lesions were diagnosed as NMSCs in 12 cases (9 BCC, 1 SCC and 2 BCC/SCC); we also excised 1 melanoma and 1 atypical fibroxanthoma. In the majority of cases, we observed a concordance between the histological type of the first and the second neoplasia (table 4 table 4). The median time interval between the first and subsequent tumour was 1.7 years. The BCC/SCC ratio was higher for the second than for the first tumour (4.7 vs. 2.1); however, the differences were not statistically significant.

Table 4 Skin tumors observed in renal transplant recipients with multiple neoplasias.

* These patients developed more than two skin cancers (multiple BCCs).

Clinical parameters and risk factors

The median age at transplantation was significantly higher in patients who developed skin cancers (53 vs. 47 years; p < 0.001). Tumours arose preferentially in males (p = 0.0017). No correlations were found with skin type, family history of skin cancer and presence of freckles or SKs. Unexpectedly, cherry angiomas were less frequently noted in patients affected by cutaneous tumours (p = 0.0053). On the contrary, a significant correlation (p = 0.0003) with the presence of AKs was found.

The exogenous risk factors significantly linked were outdoor job (p = 0.0413) and unused sunscreen (p = 0.0252), whereas the frequency of sun exposure, UV lamps, past sunburns and solar lentigines were not related (table 5 table 5).

Table 5 Clinical, endogenous and exogenous factors related with risk of cutaneous tumours.

Immunosuppressive agents and skin neoplasm

The median duration of immunosuppression was significantly longer in patients who developed skin cancers (9.9 vs. 5.7 years; p < 0.0001). In particular, we observed an increase in the cumulative tumour incidence during long-term immunosuppressive therapy: 5% at 1-year after transplantation, 19.5% at 5-years, and 43% at 10-years (figure 1). No relationships were identified between skin cancer risk and a single class of drug or combination regimens. No significant correlations were identified even between cyclosporine alone and other immunosuppressants (table 6 table 6).

Table 6 Immunosuppressive agents and skin neoplasm risk.

Multivariate logistic regression

The significant variables (age at transplantation, gender, AKs, cherry angiomas, skin type, use of sunscreen, outdoor/indoor job, duration of immunosuppression) were evaluated in multivariate logistic regression (table 7 table 7). A significant correlation with development of skin cancer was maintained by: age at transplantation (p = 0.0174), duration of immunosuppression (p = 0.0011) and presence of AKs (p = 0.0005) that showed a HR of 5.8.

Table 7 Multivariate logistic regression.

Discussion

Renal transplant patients undergo long-term immunosuppressive therapy with agents such as cyclosporine, which is commonly employed even in the treatment of chronic inflammatory and autoimmune dermatological diseases. So, the indirect role of immunosuppressive therapy could explain the relatively low percentage of these pathologies in our series of KTRs. Notably, topical tacrolimus is commonly used to manage seborrhoeic dermatosis [9]. Even if recent studies [10, 11] found a high frequency of seborrhoeic dermatitis in renal transplant patients (10%), in our experience only 3.5% were affected by this dermatosis, according to data reported for the general population [12]. The fact that the majority of our patients (58.9%) consumed tacrolimus, alone or as part of their immunosuppressive regimen, could justify this low percentage, even if further studies are necessary to make firm conclusions. In our experience, the percentage of transplanted patients with cutaneous side effects related to the assumption of immunosuppressive drugs was 10.6%. This percentage is lower in respect to those reported by other authors [10, 13]; however, we considered only clinically relevant reactions, which caused an interruption or change of the therapeutic regimen.

In the literature, the frequency of HPV infections in transplant patients varies from 6 to 92%, depending on the type and duration of immunosuppressive protocols [10]. The percentage of viral warts observed in our patients was 10.3%, similar to that reported in another Italian study [13], probably due to the treatment schedule similarity. Herpes zoster was diagnosed in 2.1% of our patients; this percentage is relatively low in comparison with data reported by other authors. However, no significant differences were found stratifying data on the basis of different age groups. Herpes zoster essentially affects patients over 60 years [14], whereas the median age of our population was 50 years. Several studies report a wide variation (7-75%) in the frequency of superficial fungal infections, which are more common in tropical and sub-tropical countries [15]. In our experience, only 1.1% onychomycosis was identified.

The increased risk of skin cancer in KTRs is well-known [2, 5, 6, 16]. The most frequent cutaneous tumours are NMSCs, with an estimated 10-fold increased risk for BCC and 50-100-fold for SCC [6]. In our experience, the percentage of patients with NMSCs (24.8%) and the BCC/SCC ratio (2.6:1) are similar to those reported in studies conducted respectively in Italy [13] and Spain [16], probably due to the prevalence of III/IV skin types in these countries. Only a small percentage of our patients referred a history of frequent sun exposure or use of UV lamps. Gallagher et al. [2] found a higher prevalence (35%) of skin cancers in Australian KTRs, supporting the importance of latitude and sun exposure and of the genetic background of a population on tumour development.

The duration of immunosuppression and type of treatment could play also a role; in particular, azathioprine is associated with a higher risk of SCCs than BCCs [17, 18]. 97% of our patients underwent transplantation after the 1986, when azathioprine was frequently dropped. The percentage of patients from our series with Kaposi's sarcoma was 3.9%, as reported in other studies [19]. In our experience, melanoma affected 3.9% of patients; however, the majority of them developed a melanoma in situ or a thin melanoma, outlining the importance of a frequent dermatological follow-up to perform an early diagnosis.

Male gender, advanced age at transplantation, duration of immunosuppression, unused sunscreen, outdoor job, absence of cherry angiomas and presence of AKs were significantly related to skin cancer in univariate analysis. Age at transplantation (p = 0.0174), presence of AKs (p = 0.0005) and duration of immunosuppression (p = 0.0011) confirmed their significance in multivariate analysis. These results also emphasize the crucial role of actinic damage in the pathogenesis of cutaneous tumours in KTRs: in elderly patients, with a specific history of incorrect or prolonged sun exposure and cutaneous markers of actinic damage, the putative cancerogenetic role of immunosuppressants is strengthened: KTRs with AKs showed an about 6-fold increased relative risk of skin cancer in respect to those without AKs. These observations are in agreement with Keller et al. [20]: AKs change more frequently into SCCs in KTRs than in immunocompetent individuals. Therefore, a prolonged clinical control program is required [21] because the cumulative incidence of skin cancers increases significantly with the duration of graft [16, 20].

Even if we could not exclude a potential role of genetic alterations in transplanted patients, as reported by several authors [22, 23], our experience supported that the role of immunosuppressants in skin cancer pathogenesis is related to the length of treatment. We did not find a significant association either with drug class or with eventual modifications of the therapeutic regimen during follow up, in agreement with the most recent studies [2, 20]. Moreover, the great majority of our patients (81.2%) were treated with tacrolimus, mofetil and mTOR inhibitors regimens. Even if the evidence about the latest immunosuppressive drugs and a lower risk of cutaneous cancerogenesis has still to be confirmed, preliminary data about the second generation drugs support this hypothesis [24].

Conclusion

In conclusion, due to the prolonged life expectancy of KTRs, it is mandatory to perform accurate periodic dermatological controls, in order to identify suspicious lesions early and to reduce skin cancer incidence. Individual follow-up programs should be carried out on the basis of specific risk factor analysis, optimizing the cost-benefit ratio. Lifelong clinical controls should be programmed once a year for patients with an estimated low cancer risk, whereas a more frequent follow-up is required for patients with cutaneous markers of actinic damage, more advanced age at transplantation and long-lasting immunosuppressive treatment.

Disclosure

Financial support: none. Conflict of interest: none.

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