Skin Cancer in Solid-Organ Transplant Patient
Monday, December 01, 2014
Continued advances in solid-organ transplantation have improved
long-term mortality among transplant patients.1 More
than 140,000 organ recipients are living in the United States (US),
with a similar number of patients on a waiting list.1
However, transplantation and iatrogenic immunosuppression are
associated with adverse events and impact on morbidity, mortality,
and patients' quality of life. While there is an overall increased
risk of malignancy, skin cancers and particularly non-melanoma skin
cancers (NMSCs) are most frequently observed (Figures 1 and
2).2-4 The risk of basal cell carcinoma (BCC) and
squamous cell carcinoma (SCC) is 10 and 65 times greater compared
to non-transplant patients, respectively.5 Importantly,
the ratio of BCC to SCC is reversed among Caucasian patients,
ranging from 1:1.2 to 1:15.5-9 The rate of melanoma
among renal transplants is also 3.6 times greater compared to
immunocompetent patients.10 Kaposi's sarcoma accounted
for 79% of cancers among non-White patients in South Africa
observed over a mean follow-up period of 6.3
Figure 1. Squamous cell carcinoma
Figure 2. Keratoacanthoma
With the exception of Kaposi's sarcoma, a significant amount of
data on incidence of NMSCs and melanoma has been derived from
predominately Caucasian populations in European countries,
Australia, and the US.12-19 In contrast, limited
information addressing the extent and types of cutaneous
malignancies in transplant patients with ethnic skin has been
published thus far. One study showed a statistically significant
decrease in 3-year cumulative incidence of NMSC in African American
(AA) and Asian renal recipients as compared to Caucasians, with a
relative risk of 0.06 and 0.11, respectively.20 A
10-year retrospective analysis of 6271 heart-transplant patients
from 32 US transplant centers demonstrated an extremely low
incidence of skin cancer among non-Caucasian patients (AA,
Hispanic, Middle Eastern, Indian, Asian and Native American), which
accounted for 15% of the study population.15 A 10-year
period free of cancer among this non-Caucasian population was
99.2%.15 This data may become clinically important since
it has been estimated that Hispanics, Asians and blacks will make
up 50% of the US population by the year 2050.21
After the first NMSC, up to 80% of transplant patients will
develop second primary NMSC within 3 years.16,22,23
Furthermore, the risk of developing NMSC is cumulative after the
transplant and gradually increases with time.1 The
degree of immunosuppression is also an important risk factor. Heart
and lung transplant patients, who require higher levels of
immunosuppression, have an increased propensity to develop NMSC as
compared to renal and liver transplants.1
Fitzpatrick Skin Phototype (SPT) is an independent risk factor
for NMSC development.24-27 The most recent study showed
the cumulative incidence of SCC at 10 years to be 51% in patients
with SPT I and 8% in SPT VI.24 Non-Caucasians
constituted less than 8% of the study sample including only 11
(1.6%) AA and 26 (3.8%) Hispanic patients. Of note, no SCCs were
observed among AA and four SCCs were diagnosed in Hispanic
patients. This study also highlighted an important concept of wide
variation of SPT within a particular ethnic group. The contribution
of ultraviolet (UV) light to NMSC development is highlighted by its
greater incidence in transplant patients in Australia as compared
to other Western countries.14 UV-related risk factors in
the post-transplant period include sunburn as a child, Fitzpatrick
SPTs I through III, residing in a hot climate for more than 30
years, and significant prior UV exposure.28,29
Voriconazole, which has potent photosensitizing properties, is a
potential contributing factor. In lung-transplant patients,
duration of voriconazole therapy was an independent risk factor for
developing SCC, which can have a more aggressive
behavior.29 While the role of human papillomavirus (HPV)
in SCC pathogenesis has not been entirely elucidated, several
studies suggest its potential role. Transplanted patients harbor a
greater quantity of various HPVs - particularly the beta
type.1,30 Moreover, seropositivity to beta-type HPV37
was associated with significantly increased risk of SCC in the
post-transplant period (odds ratio 2.0, 95% confidence interval
1.2-3.4).31 Additionally, three genetic variants of
TMC8, the gene associated with epidermodysplasia verruciformis and
predisposition to development of numerous warts and SCCs, were
associated with greater seropositivity to two species of beta HPV
Significant impairment of cutaneous immunosurveillance has been
suspected to be the main culprit for the propensity to develop
multiple NMSCs and SCC in particular.32,33 However, more
light has been shed on the direct effect of immunosuppressive
drugs, irrespective of their immunosuppressive properties.
Cyclosporine diminishes the expression of tumor suppressor PTEN and
UVB-induced DNA repair, thereby facilitating UVB-driven
carcinogenesis. Similarly, in in vitro cell-culture, tacrolimus and
mycophenolate mofetil also inhibit UVB-induced repair of
cyclobutane pyrimidine dimers. Both immunosuppressant drugs also
inhibit UVB-induced apoptosis, which serves as a major checkpoint
in preventing uninhibited proliferation of
keratinocytes.34 Azathioprine causes oxidative DNA
damage in conjunction with UVA light.35
Thus far, there has been a lack of effective and consistent
management strategies for patients with numerous NMSCs.
Pre-emptive, frequent patient monitoring with surgical or
non-surgical interventions is the current mainstay of treatment.
However, besides reduction of immunosuppression, few systemic
agents diminish the overall tumor burden. Mammalian target of
rapamycin (mTOR) inhibitors are potentially helpful in reducing the
development of SCCs. Five prospective clinical trials highlighted
the ability of sirolimus to diminish the incidence of
NMSC.36 Earlier transition to mTOR inhibitor-based
immunosuppressive regimen may be more
chemopreventative.37 Two large, randomized controlled
clinical trials showed significant reduction of NMSC incidence in
those patients who were switched to an mTOR inhibitor after their
first NMSC.28,38,39 However, there is considerable
incidence of side effects with up to 40% of patients discontinuing
mTOR inhibitors, which limits its use.36
Further research efforts are needed to better understand the
underlying pathophysiology of NMSCs in this patient population and
to identify potential targets for prevention and treatment. In the
interim, patient education and continued close surveillance are
essential aspects of patient management (Figure 3).
Figure 3. Approach to history and physical exam of a new
solid-organ transplant patient
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