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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