EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Solid-organ transplant recipients have a high risk of developing nonmelanoma skin cancers. This study sought to determine the incidence of skin cancer and identify possible risk factors for skin cancer in kidney transplant recipients.

Materials and Methods: Nonmelanoma skin cancer was diagnosed and confirmed with histology in 33 of 1275 kidney transplant recipients (2.6%). Demographic and clinical findings were reviewed retrospectively.

Results: Nonmelanoma skin cancers included squamous cell carcinoma in 10 patients (30%), basal cell carcinoma in 9 patients (27%), Kaposi sarcoma in 9 patients (27%), squamous cell carcinoma in situ in 3 patients (9%), and cutaneous lymphoma in 2 patients (6%). The ratio of squamous cell carcinoma to basal cell carcinoma was 1.1:1. The mean time from transplant to skin cancer diagnosis was 65 ± 55 months (range, 0-180 mo). Immuno-suppressive therapy was based on cyclosporine in 22 patients (67%), tacrolimus in 8 patients (24%), and combination therapy (cyclosporine and azathioprine) in 3 patients (9%).

Conclusions: Nonmelanoma skin cancer is an important clinical problem in kidney transplant recipients. Interventions that may benefit kidney transplant recipients may include intensive patient education, protection against sun exposure, and dermatologic screening programs.

Key words : Basal cell carcinoma, Immunosuppressive therapy, Kaposi sarcoma, Squamous cell carcinoma

Organ transplant may help to improve the quality of life and duration for patients who have end-stage organ failure. However, organ transplant recipients have a 3- to 4-fold increased risk of developing systemic and cutaneous cancer than the general population.^1,2 Nonmelanoma skin cancer is the most common cancer in kidney transplant recipients.^3,4 The main risk factors that predispose to skin cancer include the use of immunosuppressive drugs, viral infections, sunlight exposure, older age at transplant, and male sex.^5-11

This study sought to determine the incidence of skin cancer and identify the risk factors for skin cancer in kidney transplant recipients at a kidney transplant program in Turkey.

Materials and Methods

Patients
Patients with a diagnosis of skin cancer, confirmed with histology, were selected from 1275 kidney transplant recipients who were treated from January 1990 to December 2012 at Başkent University. The study was approved by the ethics committee of the university. Demographic and clinical findings were evaluated including age, sex, immunosuppressive therapy, age at transplant, and the time from transplant to tumor development.

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA). Data were reported as mean ± SD and analyzed with Kruskal-Wallis test and Mann-Whitney U test. Statistical significance was defined by P ≤ .05.

In 1275 kidney transplant recipients, nonmelanoma skin cancers were diagnosed in 33 patients (2.6%), mostly male recipients of living-related donor transplants (Table 1). The primary kidney disease before transplant most frequently was tubulointerstitial nephritis, glomerulonephritis, or polycystic kidney disease (Table 1). Mean age at transplant was 38 ± 14 years (range, 11-64 y) and the mean time from transplant to skin cancer diagnosis was 65 ± 55 months (range, 0-180 mo). Skin cancers were most commonly located at the head and neck (Table 1).

Most patients who developed skin cancer received cyclosporine for immunosuppression
(Table 1), and all 33 patients were receiving corticosteroids. There was no significant difference in mean time from transplant to tumor diagnosis between different immunosuppressive regimens (Table 1). In all patients, blood levels of immunosuppressive drugs were normal during the year before tumor diagnosis. In the 33 patients, acute rejection was observed in 10 patients (30%) and chronic rejection was observed in 8 patients (24%).

The most common histologic diagnoses were squamous cell carcinoma, basal cell carcinoma, and cutaneous Kaposi sarcoma (Table 2). There were 2 patients who had cutaneous lymphoma (cutaneous B cell lymphoma, 1 patient; cutaneous CD30+ T cell lymphoma, 1 patient). The ratio of frequency of squamous to basal cell carcinoma was 1.1:1 (Table 2). There were 9 patients (27%) who had intense sun exposure because of their work. In the 33 patients who were treated for skin cancer, 5 patients (15%) had local or regional recurrence within 1 year of diagnosis (3 patients had Kaposi sarcoma, and 2 patients had squamous cell carcinoma).

In the 9 patients that had Kaposi sarcoma, histologic examination of the biopsy specimens showed tumor stage in 4 patients (Figure 1), plaque stage in 3 patients, and patch stage in 2 patients. In 6 of the 9 Kaposi sarcomas (67%), positive immuno-histochemical staining for human herpesvirus 8 was noted (Figure 1). In 6 patients who had Kaposi sarcoma (67%), immunosuppressive therapy was based on cyclosporine. Most Kaposi sarcomas were in males and on the limbs (Table 2).

The mean age at transplant and the time from transplant to skin cancer presentation were significantly lower in patients who had Kaposi sarcoma than squamous or basal cell carcinoma (Table 2). Most squamous and basal cell carcinomas occurred on sun exposed areas of the skin (Table 2). There were no significant differences in sex, donor type (living-related or deceased-donor), primary kidney disease, or immunosuppressive treatment between the tumor types or between different times from transplant to skin cancer diagnosis, and there was no difference in the time from transplant to skin cancer diagnosis between patients who did or did not have graft rejection (data not shown).

Kidney transplant recipients have an increased risk of developing skin cancer compared with the general population.^1,2 However, the incidence of skin cancer after transplant varies from 2% to 30%.^3-8 This variation may be caused by differences in the level of sun exposure. Patients living in a temperate climate may have a much lower risk of developing skin cancer compared with patients living in areas with high levels of sun exposure. A higher incidence of skin cancer has been observed in northern Europe and Australia (10%-45%).^8-13 In the present study, the incidence of skin cancer was 2.6%.

The success of solid-organ transplant is possible because of immunosuppressive therapy. This therapy may prevent acute allograft rejection. Various immunosuppressive regimens are available, depending on the patient’s general condition, type of organ transplant, and the transplant center. All immunosuppressive treatments may impair the immune system network of cells and cytokines in the skin and may increase the risk of developing skin cancer.¹⁰ This may occur by 2 distinct mechanisms. Immunosuppressive agents used in transplant may be directly carcinogenic.^2,14-15 In addition, chronic immunosuppression may cause impaired immune surveillance and may prevent the eradication of precancerous changes.^2,16-18 Therefore, immuno-suppressive treatment in kidney transplant recipients is an important risk factor for developing skin cancer.

The incidence of nonmelanoma skin cancer may be greater in patients who receive cyclosporine than azathioprine or tacrolimus,^13,18-20 but some studies have shown no significant difference in the incidence of skin cancer between patients who received azathioprine or cyclosporine therapy.^1,8,21-23 In the present study, different combinations of immuno-suppressive therapies were given to kidney transplant recipients, and there were no significant differences in histologic subtypes of tumors, time from transplant to skin cancer diagnosis, or prognosis between patients having different immunosuppressive treatment.

Other risk factors for skin cancer may include sex, and men may have greater risk of developing skin cancers than women.^3,6 In the present study, most patients were men (Table 1), similar to previous studies. Age also may be an important risk factor for the development of skin cancer after transplant, with a reported 12-fold greater risk in patients aged > 55 years compared with patients aged < 35 years at transplant.²⁴ Although some studies have reported similar findings,^3,4,8,20 other studies have not shown the same association.^6,7 The mean age at transplant in the current study was 38 ± 14 years, and the age at transplant was significantly lower in patients who developed Kaposi sarcoma than epithelial skin malignancies (Table 2). The mean time from transplant to skin cancer diagnosis may vary from 48 to 108 months,^12,21,25 similar to the time observed in the present study (65 ± 55 months). For Kaposi sarcoma, the mean time from transplant to skin cancer diagnosis was shorter than for other cancers (Table 2).

In the general population, basal cell carcinoma is more frequently seen than squamous cell carcinoma. However, cutaneous squamous cell carcinoma is more frequent than basal cell carcinoma in kidney transplant recipients.^5-7,26 Some studies have reported higher ratios of basal to squamous cell carcinoma in kidney transplant recipients.^3,8,20,27 In the present study, squamous and basal cell carcinoma had similar frequency (ratio of squamous to basal cell carcinoma, 1.1:1). There were no significant differences in sex, age at transplant, and immuno-suppressive treatment between patients who developed squamous or basal cell carcinoma, and both squamous and basal cell carcinoma occurred on sun exposed areas of the skin.

Kidney transplant recipients may be susceptible to infectious diseases because of the use of immunosuppressive therapy. Several viruses may be increase the risk of cancer in kidney transplant recipients, such as Epstein-Barr virus, human herpesvirus 8, and human papilloma virus.^8,9 Kaposi sarcoma is a vascular neoplasm that contains atypical spindle cells and vascular spaces that are lined with endothelium, located primarily in the skin. Kaposi sarcoma has 4 epidemiologic types: classic, African endemic, Kaposi sarcoma associated with acquired immunodeficiency syndrome, and iatrogenic (associated with immunosuppressive drugs).¹⁰ Although Kaposi sarcoma is uncommon in the general population, organ transplant recipients have an increased risk of developing Kaposi sarcoma because of immunosuppressive therapy. This tumor is associated with Kaposi sarcoma-associated human herpesvirus (also known as human herpesvirus 8).¹⁰ The risk of Kaposi sarcoma in transplant recipients parallels human herpesvirus 8 seroprevalence in different countries and regions, which ranges from 0.4% to 13.3% (lower in Japan and northern countries and higher in Africa).²⁸ In the present study, the frequency of Kaposi sarcoma was 0.7% in all 1275 kidney transplant recipients, but similar to the frequency of basal cell carcinoma (Table 2). The age at transplant and time from transplant to skin cancer diagnosis were significantly lower in patients who had Kaposi sarcoma than those who had squamous or basal cell carcinoma (Table 2). Although Kaposi sarcoma most commonly occurs in the limbs, squamous and basal cell carcinoma were most frequently seen in the head and neck (Table 2). However, there was no difference in the cause of renal failure, type of immunosuppressive treatment, or sex between patients who had squamous cell carcinoma, basal cell carcinoma, or Kaposi sarcoma.

In conclusion, nonmelanoma skin cancer is an important problem after kidney transplant, which may lead to morbidity and mortality. Interventions that may benefit kidney transplant recipients may include intensive patient education, protection against sun exposure, and dermatologic screening programs.

Volume: 12 Issue: 3 June 2014

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