Cutaneous neoplasms in renal transplant recipients

ARTICLE

Skin cancer is the most common malignancy in renal transplant recipients, comprising 30-65% of all post-transplantation malignancies [1-3]. Cumulative lifetime incidence of any skin malignancy varies by study and by geographic region from 1.4-15.0% [4]. Up to 43% of skin malignancies present at multiple sites [1, 5], with a mean of 5.3 malignant lesions per patient with a malignancy [5]. Skin cancers in transplant recipients are characterized by presentation in younger patients (mean age 45-52) and by a more aggressive natural history, compared to the general population [5-7].

The risk ratio of any skin cancer in transplant recipients compared with the general population is as high as 20 in some studies. Many types of skin cancer occur more commonly in transplant recipients than in the general population. Incidences from a variety of studies have been summarized in Table I. The incidence of melanoma is approximately the same as in the general population [1, 2, 6, 8, 9], but most non-melanoma skin cancers are much more common in transplant recipients. The incidence of squamous cell carcinoma (SCC) in recipients is sufficiently increased compared to basal cell carcinoma (BCC) so as to reverse the typical SCC:BCC ratio seen in normal patients - a change from 1:4 to 2:1 or more. Other skin malignancies with increased incidence post-transplant include Kaposi's sarcoma, anogenital carcinomas, carcinoma of the lip, sweat gland cancer, and Merkel's cell carcinoma.

Many risk factors for development of pre-malignant and malignant lesions are the same as those in the general population. Therefore, preventive maintenance is of utmost importance. In addition, increased vigilance is required on the part of patients and health care providers to diagnose and treat such lesions promptly.

Pre-malignant lesions

Prevalence of dysplastic lesions was found to be 20% in transplant recipients in one small study [10]. Keratotic lesions are even more common, occurring in the majority of patients [11]. In one study, condylomata were found in 77%, and keratoses in 38% of transplant recipients followed for five years or more post-transplant [12]. Those who subsequently developed either SCC or BCC typically had 100 or more keratotic lesions [11]. The type of keratotic lesion cannot be identified consistently, given that many have a similar appearance on physical exam. Because of the comparatively high rate of malignant transformation compared with the general population, these lesions should be monitored and treated more aggressively.

There is a strong relationship between these lesions and the development of non-melanoma skin cancer, with an adjusted odds ratio of 20.8 when associated with over 100 keratotic lesions [13]. This risk is slightly higher for SCC, and slightly lower for BCC. While some but not all studies show a significant link between sun exposure and keratotic lesions, the link between keratotic lesions and future skin malignancy is a strong one [13, 14].

Other benign or pre-malignant lesions that appear more frequently in transplant recipients include keratoacanthoma, papillomata, molluscum contagiosum, Bowen's disease, and acne lesions [4, 5, 15]. Data on many of these lesions are lacking in the transplant population, so their natural histories are not well-defined.

Malignant lesions

Risk factors

Much of the available information on post-transplant malignancy comes from data collected in various tumor registries. The Cincinnati Transplant Tumor Registry (CTTR) is the largest of these, and has collected data worldwide on nearly 12,000 patients since 1968 [1]. Other smaller registries exist in Scandinavia, the Netherlands, Australia, and New Zealand, providing data on more localized patterns of disease [2, 16, 17]. It is therefore not surprising that marked variations in patterns of risk are reported in different regions [5, 7, 12, 14, 15, 17-19]. Unless otherwise noted, analysis of risk factors has been historically limited to the study of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), given the much more limited numbers of renal transplant patients with rarer forms of cutaneous malignancy.

Risk factors for skin malignancy following renal transplantation include

- Sun exposure: A significant risk for skin malignancy in the general population, cumulative sun exposure is an even stronger risk in transplant recipients [11, 13, 17]. There is a clear relationship between sun exposure and risk of skin cancer, one that is more pronounced in regions of the world where sun exposure is high. Figure 1 demonstrates that transplant patients in the Netherlands have an elevated risk of skin cancer after transplantation. In Australia where sun exposure is much more pronounced however, the risk of subsequent skin malignancy is markedly higher [6, 11, 17].

- Viral infection: Viral infection plays an etiologic role in the development of many post-transplant malignancies including those of the skin. This is especially true of malignancies such as anogenital carcinoma, which is preceded by condyloma acuminatum in up to 40% of patients, and lip cancer [1]. Immunosuppression appears to play a permissive role in the pathogenesis of viral infections, including infections that predate malignant lesions such as human papilloma virus (HPV). Nucleotide sequences of HPV are often found in condylomata, and occasionally in SCC of transplant recipients [11, 12]. There may also be an oncogenic interaction between sunlight and viral infection in the immunosuppressed patient [13].

- Age at transplantation: Increasing age is associated with an increased risk for skin malignancy in most studies [20] of transplant recipients.

- Gender: There appears to be little significant gender preference in most post-transplant skin cancers, though lip cancer occurs more frequently in women, and non-melanoma skin cancer occurs more frequently in men in some studies [1, 2, 6, 16, 17, 19].

- Genetic factors: Very little evidence for genetic risk factors exists, despite a collection of studies revealing significant genetic risk factors for skin malignancy in the general population. An example of genetic studies with negative results is the analysis of p53 polymorphisms in HPV-related skin tumors [20, 21] in transplant recipients.

- Allograft mismatch: Long-term antigenic stimulation by an incompletely matched allograft is thought to play a role in many post-transplant malignancies. A higher degree of antigen mismatch of the transplanted kidney was associated with increased risk of SCC in a study by Bouwes Bavinck et al. [11]. They studied 66 skin malignancies in 764 transplant recipients, and reported an odds ratio of 2.6 for single antigen mismatches and 5.0 for two-antigen mismatches. In other studies, host HLA homozygosity and donor HLA mismatching predispose to tumors which are virally induced [22, 23].

- Immunosuppression: Immunosuppressive medications clearly increase the risk of skin cancer. With few exceptions, skin malignancies in transplant recipients occur de novo following transplantation. A portion of the increased risk associated with higher degree of allograft mismatch may be explained by increased total immunosuppression in these patients. While data on discontinuation of immunosuppressive medications is limited, cessation of these medications appears to slow or even reverse tumor growth. In a small study of six transplant patients whose immunosuppression was discontinued due to allograft failure, four experienced marked improvement in overall skin condition

including resolution of verrucae [24]. Discontinuation of immunosuppressants following diagnosis of Kaposi's sarcoma has been studied in more detail and is discussed below.

- Duration of immunosuppression: Cumulative immunosuppression is associated with an increased risk for skin malignancy in most studies. Caforio et al. reported that a high rejection score at one year post-transplant, used as an indirect marker of the level of immunosuppression, was independently associated with the development of SCC [25]. Some authors have postulated that the risk of SCC may be related to cumulative immunosuppressive dosage rather than to a specific immunosuppressive drug [25, 26].

- Specific immunosuppressive medications: The choice of immunosuppressive medications does not appear to play a role in risk of skin cancer, but accurate study of such differences is limited given the rapidly evolving nature of standard immunosuppressive regimens. Existing studies are small, and include comparisons of cyclosporine to azathioprine rather than agents more commonly used today such as tacrolimus and mycophenolate mofetil [3, 6, 10, 27]. The trend in immunosuppressant usage has favored evolution towards an increasingly potent regimen. Azathioprine, used along with steroids, was the first immunosuppressant used in renal transplantation in 1969. The use of cyclosporine became widespread in the early 1980s, and over the last several years has been decreasing in favor of more potent regimens including tacrolimus and mycophenolate mofetil. During this time, the total dose of steroids decreased, and the use of irradiation was limited. These changes have resulted in significant improvements in graft and patient survival, but have made the study of transplant complications difficult. Currently, regimens using sirolimus or anti-IL-2 receptor antibody therapy will undoubtedly further complicate this picture.

Specific malignancies

Squamous Cell Carcinoma

The most common skin malignancy in transplant recipients, SCC may be so common because of its antigenic nature or because of its association with viral infection [8]. Sites of SCC in transplant recipients are confined almost exclusively to the face and dorsal aspect of the hands, the remainder occurring on the back of the neck and the forearms [17]. This clearly demonstrates the interplay among multiple risk factors, one of the most important of which is sun exposure. SCC is generally more aggressive in transplant recipients, with a higher risk of metastasis [7]. The likelihood of metastasis is still relatively low (4% in one study [6]), but all of these patients died from metastatic disease. This is in contrast to metastatic SCC in the general population, which is less common (1-2% of SCC) and is not uniformly fatal.

Basal Cell Carcinoma

There are fewer data on BCC in the transplant literature because it is less common than SCC. Like SCC, BCCs occur predominantly on the face of transplant recipients. Unlike SCC however, secondary sites appear to be confined to the upper chest and upper back [17]. Metastatic spread is rare.

Merkel's Cell Carcinoma

This neuroendocrine tumor behaves differently in transplant recipients compared to the general population [28]. In transplant recipients, it occurs at a younger age, is more aggressive (68% had nodal metastases on presentation), and is fatal in 56% of cases. 45% of these patients had additional skin malignancies.

Kaposi's Sarcoma

As in the general population, human herpesvirus-8 (HHV-8) is associated with over 95% of Kaposi's Sarcoma (KS) lesions studied in transplant recipients. The incidence of KS in allograft recipients varies by region and ethnicity, with a cumulative incidence of up to 6%. There is an overall male preponderance (2:1 to 4:1 compared with 15:1 in the general population). Kaposi's Sarcoma in transplant recipients appears to originate predominantly from previous infection with HHV-8, rather than new infection after transplantation [29]. The cumulative incidence of KS in transplant recipients is as high as 28% in patients with previous HHV-8 infection. Sexual transmission likely represents one of the principle routes of infection, though properties of HHV-8 transmission have yet to be elucidated in humans [30]. There is evidence that the virus can be transmitted from donor to recipient at the time of transplantation, though this likely represents a small fraction of HHV-8 cases [29]. A small percentage of transplant recipients seroconvert after transplant however, and donor-to-recipient transmission may be responsible for some of these cases. In one study of 287 transplant recipients, 2% seroconverted following transplantation [31]. None of these patients developed KS over the three-year follow-up, though KS can take several years to develop post-transplant, even in patients with prior infection.

Depending on the clinical presentation of KS, reduction or discontinuation of immunosuppressive medications can be a viable treatment option. KS typically regresses after such a reduction, but the reduction leads to allograft loss in approximately half of patients [30, 32]. Additional treatment with radiation and chemotherapy is often required, though this combination of therapies results in complete or partial responses in many patients so treated [33-35]. Once immunosuppression is reinstated (e.g. with a second allograft), KS usually, but not universally recurs [36].

Preventive maintenance and risk reduction are of utmost importance in transplant recipients, especially so in skin malignancy. Patient involvement here is crucial, and education, sun avoidance, use of sunscreens, and self exams are examples of such preventive measures. Similarly, physicians treating transplant recipients must be diligent; frequent and thorough physical exams and aggressive treatment of premalignant lesions are both essential. Depending on the type of malignancy and its clinical course, reduction or discontinuation of immunosuppressants is a viable option, albeit one with a significant risk of allograft loss. There may be a role for use of systemic retinoids for prophylaxis of skin cancer in patients with multiple skin cancers or in those with extensive skin dysplasia. A recent study evaluating the use of daily low-dose acitretin in 16 transplant recipients resulted in a significant reduction in skin cancers in patients receiving treatment over a five-year follow-up [37]. Trials such as this are rare, but are an example of ongoing research directed at risk reduction in this population of high-risk patients.

Article accepted on 29/8/02

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