34 Cutaneous Disease in Kidney

Transplantation Patients
ANNE LOUISE MARANO, JOANNA HOOTEN, and
SARAH A. MYERS

CHAPTER OUTLINE Introduction Corticosteroids

Cutaneous Malignancy in Renal Azathioprine
Transplant Patients Cyclosporine
Nonmelanoma Skin Cancer Mycophenolate Mofetil
Epidemiology and Pathogenesis Tacrolimus
Melanoma Sirolimus and Everolimus
Epidemiology and Pathogenesis Premalignant and Benign Cutaneous
Merkel Cell Carcinoma Tumors in Renal Transplant Patients
Epidemiology and Pathogenesis Actinic Keratosis
Rare Cutaneous Malignancies Seborrheic Keratosis
Atypical Fibroxanthoma and Porokeratosis
Undifferentiated Pleomorphic Sarcoma Infections and Inflammatory Cutaneous
Kaposi Sarcoma Findings in OTRs
Immunosuppressive Drug Considerations Cutaneous Infections
Sirolimus and Everolimus Viral Infections
Voriconazole Fungal Infections
Conclusion on Cutaneous Malignancy in Common Inflammatory Disorders
OTRs Conclusion
Immunosuppressive Drug Cutaneous Side
Effects

Introduction
Organ transplant recipients (OTRs), which include renal
transplant patients, are significantly affected by cutaneous
disease as a result of a prolonged immunosuppressed state.
Renal transplant recipients have a 5-year survival rate
of 85%.1 Therefore with promising odds for survival, the
chronic nature of skin disease may become challenging to
manage for these patients. Because the skin is visible, cuta-
neous disease may significantly affect patient quality of life.
Renal transplantation is also unique in that the return to
hemodialysis is an option, so the risks and benefits of side
effects of transplantation and the immunosuppression regi-
men must be heavily weighed if the skin cancer burden is
extreme or life threatening.
In terms of cutaneous disease, the most significant and
burdensome complication of organ transplantation is skin
cancer.1 The transplant physician should be aware of the
importance of evaluation for cutaneous malignancy in the
pretransplant and posttransplant periods. This chapter will
discuss the approach to OTRs with cutaneous malignancy.
In these patients, the transplant physician and derma-
tologist should work closely together for the benefit of the
patient. Understanding the risk factors in posttransplant
578
skin cancer is vital to the care of these patients for targeted
screening and prevention. The International Transplant
Skin Cancer Collaborative (ITSCC) and the Transplant Skin
Cancer Network (TSCN) are valuable resources for further
information on this topic.2
In addition, OTRs often demonstrate increased rates of
premalignant and benign cutaneous tumors, and infec-
tious and inflammatory cutaneous conditions. These will
be discussed in this chapter; however, the main focus of this
chapter is to inform the transplant physician on the press-
ing matter of cutaneous malignancy in OTRs. 
Cutaneous Malignancy in Renal
Transplant Patients
NONMELANOMA SKIN CANCER
Epidemiology and Pathogenesis
OTRs are at an increased risk of malignancy compared
with the general population because of immunosuppres-
sion. Skin cancer is the most frequently reported posttrans-
plant malignancy. In particular, nonmelanoma skin cancer

TABLE 34.1  Risk Factors for Development of Skin
Cancer in Organ Transplant Patients
Fitzpatrick skin type I to III
Increasing age at transplantation
Duration and level of immunosuppression
Type of organ transplant (heart/lung > kidney > liver)
Previous transplant
Squamous cell carcinoma before transplant
History of lymphoma pre-/posttransplant
Pretransplant end organ disease (e.g., rheumatoid arthritis, systemic
lupus erythematosus, or autoimmune hepatitis)
Liver transplant recipients with psoriasis on previous biologic therapy/
psoralen plus ultraviolet A light phototherapy
From Zwald F, Brown M. Skin cancer in solid organ transplant recipients:
advances in therapy and management: Part 1. Epidemiology of skin cancer
in solid organ transplant recipients. J Am Acad Dermatol 2011;65:253–61.
(NMSC) represents 95% of posttransplant skin cancer.1 The
incidence of posttransplant skin cancer has been reported at
1427 per 100,000 person-years.2 Interestingly, in the gen-
eral population, basal cell carcinoma (BCC) is the most com-
mon type of NMSC and squamous cell carcinoma (SCC) is
the second most common type of NMSC, whereas the ratio
in the OTR population is reversed. Organ transplantation
increases the risk of cutaneous SCC by 65-fold and BCC by
10-fold.1 Furthermore, SCC is more likely to be aggressive
in OTRs. Specifically, in the general population, the risk
of metastasis of SCC is 0.5% but increases to about 8% for
OTRs.1
The factors associated with risk of NMSC posttrans-
plant include the following: Fitzpatrick skin type I or II
(fair skin), increasing age at transplantation, duration
and level of immunosuppression, type of organ transplant
(heart and lung > kidney > liver), previous transplant, his-
tory of SCC pretransplant, history of lymphoma, pretrans-
plant end-organ disease (rheumatoid arthritis, systemic
lupus erythematosus, autoimmune hepatitis), and liver
transplant recipients with a history of psoriasis on previ-
ous biologic therapy or psoralen plus ultraviolent A light
(Table 34.1). To simplify risk stratification, a recent study
from the TSCN from 26 centers with more than 10,000
patients identified the following statistically significant
risk factors for posttransplant skin cancer: pretransplant
skin cancer, male sex, white race, and age at transplant
50 years or older.2
An additional predictive index was developed for a com-
prehensive and cost effective targeted surveillance strategy
for skin cancer in renal transplant patients so that those at
high risk can be easily recognized early on posttransplant.3
Patient age, outdoor exposure, ultraviolet light exposure,
pretransplant skin cancer, childhood sunburn, and skin
type were selected as predictors.3 A score >7 was designated
as high risk for NMSC within 2 years, and of these patients,
the chance of being SCC-free at 2 years was 43%, and at 5
years was 17%. In contrast, with a score <4, 99% were free
from SCC at 6 months, 95% at 2 years, and 89% at 5 years.3
The direct association of duration and degree of immu-
nosuppression with the risk of NMSC in OTRs suggests
that immunosuppression is key to the pathogenesis of
NMSC in OTRs. The pathogenesis of NMSC is multifacto-
rial. Ultraviolet light causes genetic mutations, in particu-
lar in the p53 gene in SCC, and these mutations eventually
34 • Cutaneous Disease in Kidney Transplantation Patients 579
accumulate and lead to carcinogenesis.4 This is supported
by the fact that NMSC in OTRs is associated with latitude
and that Australian OTRs have a higher risk of NMSC than
patients in England.4 Ultraviolet light causes a charac-
teristic type of mutation, resulting in cytosine to thymine
transitions through the formation of cyclobutane dimers,
which are commonly found in NMSC p53 mutations.4 The
immune system normally functions to provide surveil-
lance and eliminate precancer.4 This is evidenced by the
effectiveness of immunomodulatory medications, such as
imiquimod, in treating premalignant actinic keratosis. In
addition, the immunosuppressive medications themselves
may be directly carcinogenic, the most prominent exam-
ple of which is azathioprine.4 Cyclosporine may also be
carcinogenic.4
More recently, the role of the human papillomavirus
(HPV) infection in OTRs in NMSC pathogenesis has become
more widely appreciated.5 OTRs have greater quantities of
HPV deoxyribonucleic acid (DNA) found in SCC samples.1
HPV viral proteins E6 and E7 are oncoproteins involved
in regulating cell cycle checkpoints.6 This may also be
observed clinically in the warty appearance of many SCC in
OTRs. Of consequence, a recent study found that NMSC in
nonwhite OTRs was more likely to occur in nonsun-exposed
areas, in particular, on the genitals.7 This is suggestive of
the role of sexually transmitted HPV in NMSC in nonwhite
OTRs.7 The value of pretransplant or posttransplant HPV
vaccination for preventing NMSC has yet to be studied and
warrants further investigation.8
In summary, NMSC incidence is increased in OTRs
because of immunosuppression, ultraviolet carcinogenesis,
drug carcinogenicity, and possibly because of HPV infec-
tion, particularly in nonwhite OTRs.
Clinical Presentation. SCCs may vary in clinical appear-
ance, but as previously noted, they are the most prevalent
skin cancer in OTRs; therefore any suspicious growing
lesion should be biopsied. In general, both BCC and SCC
commonly arise on sun-exposed areas of the body. SCCs are
often erythematous, keratotic plaques that may also ulcer-
ate (Fig. 34.1). The subtype of keratoacanthoma is a cra-
teriform appearing SCC that is rapidly growing. SCCs are
often tender. BCCs are classically described as “pink, pearly
papules” but may also become ulcerated.
Field cancerization is a term that describes a heavy bur-
den of cancer in an area or “field” of skin. It commonly
refers to extensive areas of sun damage with multiple kera-
totic neoplasms including actinic keratosis, SCC in situ, and
SCC. Both “transplant hands” (Fig. 34.2) and “transplant
scalp” are common descriptors of field cancerization in the
OTR population.
In general, physical examination should be performed
of the draining lymph node basins in transplant patients
with a high-risk SCC. SCCs can be aggressive, metastasizing
to the lymph nodes, and can cause death. The risk of local
recurrence of high-risk SCC is 13.4%, usually within the
first 6 months after excision.9 The risk of metastasis of SCC
in the general population is 0.5 to 5%. The risk increases to
8% for OTRs.10 This is a poor prognostic sign, with a 3-year
overall survival for OTRs with metastatic SCC of 48%.4 In
contrast, BCCs rarely metastasize but can be locally aggres-
sive and cause physical destruction.
580 Kidney Transplantation: Principles and Practice
Fig. 34.1  Squamous cell carcinoma on the left temple.
Fig. 34.2  Field cancerization on the hands, also known as transplant
hands.
In SCC, high-risk features include the following: large size
>2 cm, high-risk location (ear, lip, scalp, temple), tumor
depth >2 mm, recurrent, poor differentiation, perineural
invasion, and lymphovascular invasion1,11 (Table 34.2).  Capecitabine, a prodrug of 5-deoxy-5-fluorouridine, is
Management. The management of NMSC in OTRs
involves prevention, treatment, and surveillance. Of these,
prevention is of the utmost importance and should begin
in the pretransplant evaluation. Prevention also includes
continued education on sun protective measures and on
self-skin examination. In severe cases, prevention may
TABLE 34.2  High-Risk Features of Squamous Cell
Carcinoma in Organ Transplant Patients
Large size (>2 cm)
Multiple squamous cell carcinomas
High-risk location (ear, lips, over parotid gland, scalp, or temple)
In-transit metastatic lesion
Recurrence
Histology
Poorly differentiated
Perineural invasion
Deep invasion
From Zwald F, Brown M. Skin cancer in solid organ transplant recipients:
advances in therapy and management: Part 2. Management of skin cancer
in solid organ transplant recipients. J Am Acad Dermatol 2011;65:263–79.
also involve chemoprevention with medication, which
will be discussed later. The treatment of NMSC in OTRs is
often complicated in that the risks and benefits of various
medical and surgical procedures must be weighed. Sur-
veillance is particularly important for SCC, which has a
higher rate of metastasis in OTRs compared with the gen-
eral population.10 
Prevention. Chemoprevention may be used in OTRs with
numerous NMSCs. The options are discussed later. Reti-
noid derivatives, such as acitretin, have been shown to be
effective in the suppression of SCC development, includ-
ing reduction in actinic keratoses and SCCs.12 Indications
for the initiation of systemic retinoids in organ transplant
patients are the following: development of multiple SCCs
per year (5–10/year); development of multiple SCCs in
high-risk locations (head/neck); patients with a history of
lymphoma/leukemia and SCCs; a single SCC with high met-
astatic risk; metastatic SCC; explosive SCC development;
and eruptive keratoacanthomas.13 Low-dose acitretin (10
mg) therapy should be started to minimize side effects with
slow titration by 10 mg increments at 2- to 4-week inter-
vals to the target dose of 20 to 25 mg daily. Side effects are
dose related, with dry eyes and mouth being the most com-
mon; dry skin and pruritus are less common. Acitretin is a
known teratogen (pregnancy category X) and its use should
be carefully considered in childbearing women who wish
to conceive within 3 years. Severe hyperlipidemia that is
refractory to standard treatment is a contraindication. Lab-
oratory monitoring must be performed frequently, includ-
ing a baseline pregnancy test, complete blood count, fasting
lipid panel, liver panel, and serum creatinine. Chemopre-
vention with oral retinoids is a lifelong treatment. When
the medication is discontinued, a rebound effect occurs that
is difficult to control. Patients can experience the eruption
of multiple aggressive SCCs over a relatively short period
of time. Thus reduction of the dosage of acitretin is usually
successful at maintaining patient compliance while still
benefiting from chemoprevention.14
metabolized by the liver to 5-FU and is less commonly used
for NMSC chemoprevention. Initially used for the treatment
of metastatic breast and colon cancer, the use of systemic
5-FU has been shown to be beneficial in reducing the devel-
opment of precancerous and cancerous lesions in organ
transplant patients.14 In a retrospective review performed
at the University of Minnesota,15 organ transplant patients

who were given low-dose capecitabine had lower rates of
developing NMSC and actinic keratoses compared with the
period before capecitabine treatment. However, grade 3
and 4 toxicities were common, causing discontinuation.15
Prospective studies are needed to determine the long-term
efficacy and safety of lower doses.
More recently, a randomized controlled trial demon-
strated efficacy of nicotinamide in preventing NMSC.16 This
offers an appealing alternative to acitretin or capecitabine
because of a limited side effect profile for nicotinamide. This
study was not performed in OTRs but included patients with
at least two NMSC in the previous 5 years. Patients received
nicotinamide 500 mg twice daily or placebo for 12 months.
At 12 months, the rate of new NMSC was lowered by 23%
in the nicotinamide group compared with the rate of new
NMSC in the placebo group.16 The efficacy of nicotinamide
in reducing NMSC in OTRs requires further study.
Overall, patient education on sun protective behaviors
and early signs of skin cancer is very important in the
OTR population. Specifically, patients should be taught
to use daily broad-spectrum sunscreen, protective cloth-
ing, and avoidance of sun tanning and tanning beds. A
helpful resource for patients and clinicians is the ITSCC
patient education brochure “After Transplantation -
Reduce Incidence of Skin Cancer” (AT-RISC Alliance:
http://at-risc.org/).  bony invasion, possible orbital invasion, for assessment of
Treatment. Topical therapies are used for precancer-
ous actinic keratosis, BCC, and SCC. In particular, topical
therapies may be appropriate for the superficial variant of
BCC and SCC in-situ. 5-fluorouracil 5% cream is a topical
chemotherapy cream and imiquimod is a topical immuno-
modulatory agent that targets toll-like receptor 7. These
are effective for the treatment of actinic keratosis, super-
ficial BCC, and SCC in-situ and for chemoprevention.14
These therapies cause an inflammatory and crusted reac-
tion, which may be intolerable to patients. Some patients,
however, prefer this treatment to surgery because it does
not require a doctor’s visit and is often nonscarring. Many
male transplant patients with hair loss benefit from regu-
lar use of 5-flourouracil cream on the scalp to prevent SCC
formation.4
Photodynamic therapy (PDT) is another treatment
modality for actinic keratosis and superficial NMSC, partic-
ularly if there is a large area such as the scalp involved. PDT
involves the use of an exogenously administered precursor
of photosensitizer protoporphyrin IX synthesis (usually
either aminolevulinic acid or methyl aminolevulinate) that
is activated by light, producing reactive oxygen species and
destroying tumor cells. PDT has been effective in the treat-
ment of actinic keratosis and superficial NMSC in OTRs.4,14
PDT must be administered under physician supervision in a
clinic setting. Common side effects are pain and erythema.
The simplest surgical procedure for treatment of NMSC
is electrodessication and curettage.4,14 This is similar to a
biopsy but with the addition of three passes of electrodessi-
cation and curettage to the base of the lesion. This is a sim-
ple procedure that may be performed at the time of biopsy,
which is preferable for many OTRs with frequent doctors’
visits. The downsides are a slightly lower cure rate than
excision and often a large circular hypopigmented scar in
contrast to a linear scar from an excision.
34 • Cutaneous Disease in Kidney Transplantation Patients 581
Wide local excision or Mohs surgery are the preferred
modalities for treatment of infiltrative BCC and SCC.4,14
Wide local excision is often performed with 4-mm margins
for NMSC and a surgical pathologist subsequently evalu-
ates all of the tissue margins postoperatively. Mohs surgery
entails removing one thin layer of tissue at a time; each layer
is evaluated through frozen section histology for the pres-
ence of remaining tumor. If the circumferential and deep
margins are clear, the surgery is ended. If not, another layer
is removed from the margin where tumor was noted, and
the procedure is repeated until all margins of the final tissue
sample are clear of cancer. This offers better margin control,
minimal tissue defect, and has higher cure rates than wide
local excision. Mohs surgery is preferred for NMSC on the
face, large lesions, and recurrent NMSC.4,14
The most concerning outcome in SCC in OTRs is metas-
tasis, either to lymph nodes or systemically because of the
worsened prognosis, as mentioned earlier. The role of imag-
ing in cutaneous SCC is somewhat controversial. Patients
with palpable lymph nodes should undergo sentinel lymph
node biopsy and dissection.4,14 Otherwise, a sentinel lymph
node biopsy should be considered for OTR patients with
high-risk SCC or lymph nodes found on imaging performed
in the appropriate patient. A recent consensus article sug-
gested consideration of imaging in patients with possible
extent of tumor invasion in soft tissue, for staging evalua-
tion in high-risk SCC, for evaluation of potential perineu-
ral spread, and for postoperative surveillance for recurrent
disease.11
For metastatic SCC, medical, surgical, and radiation ther-
apies should be combined.4,14 Currently, there are limited
medical therapies for metastatic SCC and most of these have
been studied in immunocompetent patients. Radiotherapy
may also be used adjunctively.4,14 The most important
medical intervention is to decrease immunosuppression
if possible. Chemotherapy traditionally included cispla-
tin and 5-flourouracil. More recently, epidermal growth
factor receptor inhibitors such as gefitinib, erlotinib, and
cetuximab have been used to treat metastatic SCC.4,14,17,18
Furthermore, programmed cell death receptor 1 (PD1) or
its ligand (PDL1) inhibitors such as pembrolizumab and
nivolumab have been used in single patients with meta-
static SCC but there have been no randomized controlled
studies.19 Pharmaceutical companies Regeneron and
Sanofi are planning trials for cemiplimab for cutaneous
SCC.20 Importantly, the effect of using an immune check-
point inhibitor on a transplant patient’s graft function is
unknown and may be problematic.
For metastatic BCC in OTRs, there is a Food and Drug
Administration–approved medication, vismodegib. Vis-
modegib is a smoothened inhibitor in the sonic hedgehog
pathway.21 Efficacy is approximately 30% with many sys-
temic side effects including electrolyte abnormalities, alope-
cia, taste loss, and muscle cramps.21 Additionally, a recent
study showed an increased risk of SCC with vismodegib
treatment, which may be of particular concern in OTRs
with NMSC.22 Interestingly, a subsequent study did not
show an increased risk of SCC in patients on vismodegib.23
The use of vismodegib and risk of SCC remains unclear and
requires further study and careful application in the trans-
plant population. 
582 Kidney Transplantation: Principles and Practice

Surveillance. Patients with a history of NMSC and organ
transplantation should be followed-up with every 3 to 6
months, and examination should include a lymph node
examination for high-risk SCC (Table 34.3). For patients
with high-risk SCC with concerning features on follow-up
physical examination (i.e., lymphadenopathy, neurologic
signs) should undergo a positron emission tomography
(PET)/computed tomography (CT) for evaluation for recur-
rent disease.11 The frequency of long-term follow-up may
be stratified by risk3 (see Table 34.3).  tion for stage T1 and T2b, a 2-year delay after clearance of
Pretransplant Delay. From the perspective of the
transplant physician, a previous diagnosis of a cutane-
ous malignancy may affect the decision to proceed with
solid-organ transplantation. A consensus guideline from
the ITSCC was developed for recommendations regard-
ing solid-organ transplantation with a pretransplant SCC,
TABLE 34.3 Follow-Up Intervals for Total Body Skin
Examination for Solid-Organ Transplantation
Interval for Total Body Skin
Patient Risk Factor Examination (No. of Months)
No skin cancer/field disease 12
Field disease 3–6
One nonmelanoma skin cancer 3–6
Multiple nonmelanoma skin cancers 3
High-risk squamous cell carcinoma 3 ranging from a 3- to 5-fold increased risk in OTRs com-
or melanoma
Metastatic squamous cell carcinoma 1–3
or melanoma
From Zwald F, Brown M. Skin cancer in solid organ transplant recipients:
advances in therapy and management: Part 2. Management of skin cancer
in solid organ transplant recipients. J Am Acad Dermatol 2011;65:263–79.
melanoma, and Merkel cell carcinoma.24 As stated previ-
ously, one of the major risk factors for posttransplant skin
cancer is pretransplant skin cancer. For renal transplant
patients with a history of pretransplant SCC, there is a
40% to 80% chance of posttransplant SCC.24 The ITSCC
guidelines are based on the principle that a patient should
have at least a 5-year survival from malignancy of 60%
to ethically transplant an organ.24 For SCC, the consensus
panel recommends the following: no delay in transplanta-
tumor for high-risk SCC (large size >2 cm, high-risk loca-
tion [ear, lip, scalp, temple], tumor depth >2 mm, recur-
rent, poor differentiation), and a 2- to 3-year delay after
clearance for tumor for high-risk SCC with perineural
invasion24 (Table 34.4). 
MELANOMA
Epidemiology and Pathogenesis
Melanoma is an immunogenic cutaneous malignancy
with higher risk of metastasis, and its incidence continues
to increase. The relationship between melanoma risk and
organ transplantation is less clear than that for NMSC.
The transplant physician should be aware of a history of
pretransplant melanoma and screen for melanoma in the
posttransplant period.25 For melanoma, there are reports
pared with the general population.1,26 In renal transplant
recipients, a large study found a 3.6-fold increased risk of
melanoma in renal transplant recipients.27 African Ameri-
can OTRs have a 1.72-fold increased risk for melanoma.1
The mean duration from transplantation to posttransplant
melanoma is 5 years.1

TABLE 34.4  Recommended Wait Times Pretransplantation for Patients With a History of Skin Cancer Before Transplantation
Wait Time Before
Skin Malignancy Appropriate Treatment Pretransplantation Transplantation After Treatment
SQUAMOUS CELL CARCINOMA
No history of SCC but high risk for SCC Treatment of field disease No delay
Low-risk SCC Surgical excision with clear margins of Mohs micrographic No delay
surgery
High-risk SCCa other than Surgical excision with clear margins of Mohs micrographic 2 years
perineural invasion surgery
High-risk SCCa with perineural invasion or ≥2 Surgical excision with clear margins of Mohs micrographic 2–3 years
high-risk features surgery +/− radiotherapy
High-risk SCC with local nodal metastasis Surgical excision with clear margins of Mohs micrographic 5 years
surgery + radiotherapy
Distant metastasis Refer for oncology opinion Not eligible for transplantation
MERKEL CELL CARCINOMA
Local with negative sentinel lymph node biopsy Wide local excision +/− radiotherapy 2 years
Local with nodal metastasis Wide local excision, lymph node dissection + radiotherapy 3–5 years
Distant metastasis Refer for oncology opinion Not eligible for transplantation
MELANOMA
In situ melanoma Wide local excision No delay, follow-up posttransplan-
tation 3 months
Stage Ib melanoma Wide local excision 2 years
Stage Ib/IIa melanoma Wide local excision +/− sentinel lymph node biopsy 2–5 years
Stage IIb/IIc melanoma Wide local excision + sentinel lymph node biopsy 5 years
Stage III or IV melanoma Refer for oncology opinion Not eligible for transplantation
alargesize >2 cm, high-risk location (ear, lip, scalp, temple), tumor depth <2 mm, recurrence, poor differentiation, perineural invasion.
From Zwald F, Leitenberger J, Zeitouni N, et al. Recommendations for solid organ transplantation for transplant candidates with a pretransplant diagnosis of
cutaneous squamous cell carcinoma, Merkel cell carcinoma and melanoma: a consensus opinion from the International Transplant Skin Cancer Collaborative
(ITSCC). Am J Transplant 2016;16(2):407–13.

Risk factors for developing melanoma specifically in renal
transplant patients have recently been outlined in a cohort
study of a large national data registry and include older age,
male sex, recipient white race, less than four human leuko-
cyte antigens (HLA) mismatches, living donors, and siroli-
mus and cyclosporine therapy.28 Transplant clinicians can
identify these risks factors and close skin surveillance should
be provided for patients with higher risk characteristics.
Immunosuppression also appears to deleteriously affect
the course of melanoma in transplant patients. In the larg-
est study of melanoma in the OTR population, patients who
developed melanoma demonstrated worse overall survival
compared with expected survival in control subjects.29 In
addition, patients with thicker melanomas appear to have
increased risk of dying of metastatic melanoma.29 Large
multicenter studies are needed to provide better under-
standing of the role of immunosuppression on the behavior
of melanoma in OTRs.
With the advent of immunotherapy in treating melanoma,
it is known that the immune system plays a role in mela-
noma pathogenesis. The less defined relationship between
melanoma and OTR is likely due to the multifactorial nature
of melanoma pathogenesis. Melanoma risk is also increased
with ultraviolet light exposure, in particular with tanning bed
use, and genetic factors such as mutations in the p16 gene.1,26
An illustrative example of the role of immunity in melanoma
pathogenesis is the case report of a renal transplant patient
who developed metastatic melanoma from a donor kidney.30
The donor did not have clinical symptoms of metastatic mela-
noma, suggesting that the donor immune system was keep-
ing the melanoma in check. However, when the transplant
allograft was placed in a host on immunosuppressive medica-
tion, metastatic melanoma developed.30 Therefore melanoma
risk is likely related to immunosuppression but appears to be
less clearly linked than NMSC is to immunosuppression.
Clinical Presentation. In general, melanomas are pig-
mented lesions, with the exception of the rare variant of
amelanotic melanoma. The subtypes of melanoma are the
following: superficial spreading, lentigo maligna, nodular,
and acral lentiginous. The “ABCDE” acronym summarizes
the clinical features of melanoma: asymmetry, border irreg-
ularity, color variation, diameter more than 6 mm, and
evolution.31 Loss of color should also raise suspicion. Any
suspicious lesion should be biopsied, and treatment is based
on the pathology (Breslow depth ± ulceration or mitoses)
and lymph node involvement of melanoma.31 Therefore a
lymph node examination for the draining lymph nodes in
an OTR with melanoma is imperative.31  of MCC in OTRs compared with the general population.1,36
Management. Melanoma should be managed surgically
with wide local excision with consideration of a sentinel
lymph node biopsy based on the severity of the tumor. The
following surgical margins are appropriate: 5 mm for mela-
noma in-situ, 1 cm for melanoma <1 mm Breslow depth,
and 2 cm for melanoma >2 mm Breslow depth. Sentinel
lymph node biopsy should be considered for melanomas
with Breslow depth >1 mm and some argue >0.75 mm.32
A large prospective trial showed there was no survival
benefit to complete lymph node dissection in node-positive
melanoma, and this may eventually change the surgical
management of these patients, particularly in the era of
improved medical therapies.33
34 • Cutaneous Disease in Kidney Transplantation Patients 583
For metastatic melanoma, several emerging therapies
are rapidly advancing the field. BRAF inhibitors such as
vemurafenib and dabrafenib are available for metastatic
melanoma.34 In addition, immunotherapies such as ipilim-
umab and PD-1 inhibitors are being widely used in mela-
noma for the possibility of a durable response.35 The effects
of these therapies on graft function are unknown. In life-
threatening melanoma, immunosuppression changes and/
or reduction should also be considered. 
Surveillance. Patients with a history of melanoma and
organ transplantation should be followed-up with every
3 months, and examination should include a lymph node
examination and examination for in-transit metastases (see
Table 34.3). 
Pretransplant Delay. As mentioned in the NMSC section,
a consensus guideline was developed for management of
the pretransplant SCC, melanoma, and Merkel cell carci-
noma.24 For melanoma, case control studies have shown
that the immunosuppression has a differential effect on
melanoma in the context of transplantation, such that a
thin melanoma (Breslow depth 1.5–2 mm) may behave
comparably to melanoma in immunocompetent individu-
als, whereas thick melanomas (Breslow depth >2 mm) may
behave more aggressively and be associated with increased
mortality risk.24 Patients with melanoma in-situ, stage
Ia, Ib, IIa, IIb, and IIIa are considered organ transplant
candidates, but stages IIc, IIIb, IIIc, and IV should not be
considered organ transplant candidates.24 The consensus
guideline recommends the following wait time for pretrans-
plant melanoma: no delay for melanoma in-situ, a 2-year
delay after wide local excision for stage Ia melanoma, a
2-year delay after wide local excision +/− sentinel lymph
node biopsy for stage Ib/IIa melanoma, a 2- to 5-year delay
after wide local excision +/− sentinel lymph node biopsy for
stage IIb/IIc melanoma, and that stage III and IV melanoma
patients are not candidates for organ transplantation24 (see
Table 34.4). 
MERKEL CELL CARCINOMA
Epidemiology and Pathogenesis
Merkel cell carcinoma (MCC) is a rare cutaneous malig-
nancy of neuroendocrine origin, but is particularly aggres-
sive and concerning in organ transplant patients. Therefore
reduction of immunosuppression may be recommended in
OTRs who develop MCC. There is a 10-fold increased risk
MCC tends to develop 7 to 8 years posttransplant.1,36 The
pathogenesis of MCC involves ultraviolet light, demon-
strated by the increased incidence of MCC on the head and
neck, and also infection with the human polyoma virus
in the majority but not all patients. Logically, the more
aggressive nature of MCC in OTRs makes sense given its fre-
quent viral association. Overall, MCC in OTRs metastasize
to lymph nodes in 68% of cases and cause death in 56% of
cases.1,36
Clinical Presentation. MCCs do not have a distinct
appearance and are often biopsied to rule out NMSC. Many
of these lesions present on the head and neck. Lesions pres-
ent as dome-shaped pinkish-red to bluish-brown papules or
584 Kidney Transplantation: Principles and Practice
nodules and are frequently ulcerated. A full skin examina-
tion for satellite lesions, a sign of in-transit spread, and a
lymph node examination of draining lymph node basins are
necessary. 
Management and Treatment. All MCCs require surgical
treatment with wide local excision or Mohs surgery.14,37
Given the aggressive nature of MCC, all MCC in OTRs need
a sentinel lymph node biopsy performed.14,37 Management
includes surgery with a wide local excision with at least
2.5- to 3-cm margins or Mohs surgery and radiotherapy
to the site and regional lymph nodes.14,37 Immunosup-
pression may need to be reduced with MCC given the high
malignancy mortality rate of over 50%.14,37
For patients with advanced MCC, treatment is challeng-
ing. A recent phase II study demonstrated that for 26 patients
with unresectable MCC, pembrolizumab (anti-PD1) ther-
apy was used and resulted in a 56% objective response rate,
with four patients with a complete response.38 Responses
were seen in virus-positive and virus-negative tumors.38
These patients were not OTRs. Nevertheless, this may be
a promising new therapy for advanced MCC in which few
treatment options exist.  of immunosuppression but the mechanism is unclear.1,4
Surveillance. Patients with a MCC and organ transplan-
tation should be followed-up with every 3 months and
examination should include a lymph node examination
and examination for in-transit metastases (see Table 34.3). 
Pretransplant Delay. As mentioned in the NMSC and
melanoma sections, a consensus guideline was developed
for management of the pretransplant SCC, melanoma, and
MCC.24 For MCC, the consensus guidelines recommend the
following: at least a 2-year delay for patients with stage IIb
or less MCC (local disease, tumor size <2 cm, negative senti-
nel lymph node biopsy), and that patients with stage III and
higher (regional lymph node disease or metastasis) are not
organ transplantation candidates24 (see Table 34.4).  after the index posttransplant cancer were 9.3%, 20.6%,
RARE CUTANEOUS MALIGNANCIES
Atypical Fibroxanthoma and Undifferentiated
Pleomorphic Sarcoma
Atypical fibroxanthoma (AFX) is a rare spindle cell neo-
plasm that presents as a solitary pink to red nodule, usually
arising on the head and neck, often biopsied to evaluate for
NMSC. AFX is considered to be an indeterminate lesion, a
less aggressive superficial variant of undifferentiated pleo-
morphic sarcoma. In OTRs, both AFX and undifferentiated
pleomorphic sarcoma have a higher rate of local recurrence
and metastasis than in the general population.39 Treatment
should be aggressive, with Mohs surgery or wide local exci-
sion with 2-cm margins, followed by adjuvant radiation
therapy.39 
Kaposi Sarcoma
Classically, Kaposi sarcoma (KS) is associated with HIV/
AIDS but may present similarly in immunosuppressed OTR
patients. KS in OTRs is very rare.40 KS presents with viola-
ceous plaques, most often on the extremities. KS is mediated
by the herpesvirus 8.40 KS may be managed with destruc-
tion of lesions, chemotherapy, radiation therapy, but most
importantly in OTRs, by reducing immunosuppression.40  may involve the interaction of voriconazole metabolites
Immunosuppressive Drug
Considerations
The degree of immunosuppression, but also the specific
medications used, affect the risk of cutaneous malignancy
in OTRs. In general, it is preferable to minimize the number
of immunosuppressive drugs in patients with a high cuta-
neous malignancy disease burden or a high-risk cutaneous
tumor. Several studies have shown that patients receiving
triple immunosuppression (cyclosporine, prednisone, aza-
thioprine or sirolimus) were at increased risk for skin cancer
development compared with those on dual therapy (predni-
sone and azathioprine or sirolimus).1 Both azathioprine and
cyclosporine have been shown to be carcinogenic.1,4 There-
fore maintenance therapy with tacrolimus over cyclosporine
is recommended as first-line calcineurin inhibitor in combi-
nation with mycophenolate mofetil rather than azathioprine
as an antiproliferative agent. Azathioprine has mutagenic
and photosensitizing properties and sensitizes to DNA dam-
age by ultraviolet A via its metabolite 6-thioguanine.1,4
Cyclosporine is also thought to be carcinogenic independent
Details of cutaneous side effects of specific transplant
medications will be discussed in the drug side effect section.
SIROLIMUS AND EVEROLIMUS
Emerging evidence suggests that sirolimus is the preferred
immunosuppressive agent used in OTRs with high cuta-
neous malignancy burden.1 The concern with sirolimus is
that it may affect wound healing and may not be a potent
enough immunosuppressant early posttransplant.1 A ret-
rospective study showed an 11.6% reduction in skin cancer
in the sirolimus-treated versus nonsirolimus-treated group
overall. There was no difference in mortality or rejection.41
The cumulative incidence of skin cancer at 1, 3, and 5 years
and 24.7%, respectively in the sirolimus-treated group, ver-
sus 17.7%, 31%, and 35.8%, respectively in the nonsiroli-
mus-treated group, thus demonstrating a lower risk for skin
cancer with sirolimus treatment.41 In renal transplant spe-
cifically, a retrospective study showed that, compared with
mycophenolate and standard cyclosporine, everolimus
with reduced-dose cyclosporine resulted in hazard ratios
of 0.28, 0.39, and 0.41, respectively for NMSC, nonskin
cancer, and any cancer.42 There were no associations with
rejection, graft loss, or death.42 These data require further
prospective study. Additionally, there was a retrospective
study of SCC in OTRs that did not find statistical significance
for decreased SCC risk in patients taking sirolimus.43 
VORICONAZOLE
Voriconazole is a triazole antifungal medication approved
for the treatment of aspergillosis in transplant patients and is
most often used in lung transplant patients. One of the well-
established side effects of voriconazole is photosensitivity.
Voriconazole-induced photosensitivity results in a sunburn-
like erythema on sun-exposed sites.44 Voriconazole-induced
photosensitivity accelerates the risk of skin cancer post-
transplantation, but the mechanism is not understood and

with ultraviolet light.45 A large retrospective study found
an increase in cutaneous SCC in lung transplant patients
treated with voriconazole with an absolute risk at 5 years
after transplant of 28%.46 An additional large retrospective
study found that voriconazole exposure was associated with
73% increased risk of cutaneous SCC with each additional
30-day exposure at the standard dose, thereby increasing
the risk by 3%.47 The duration of voriconazole exposure has
been shown to be an independent risk factor for skin cancer
in lung transplant patients.48 This is an important consid-
eration because prolonged therapy with voriconazole may
be necessary given the chronic nature of invasive fungal
infections.45 In addition, there is concern that voriconazole-
associated cutaneous SCC in an immunosuppressed patient
may be especially aggressive, and there are reports of patients
dying from cutaneous SCC metastatic disease.49 Therefore it
is important to note voriconazole exposure as a risk factor for
developing SCC in transplant patients. 
Conclusion on Cutaneous
Malignancy in OTRs
Based upon the information just discussed, the importance of
the cooperation between a transplant physician and a derma-
tologist in the management of solid-organ transplant recipi-
ents should be evident. Even in the pretransplant period, a
dermatologist may serve a role in assessing posttransplant
risk for patients with a history of high-risk cutaneous malig-
nancies.24 A recent study suggested that patient education,
understanding, and compliance with photoprotective mea-
sures were significantly lower in patients who had never
attended a specialty OTR dermatology clinic compared
with patients being treated in a specialty OTR dermatology
clinic.50 The treatment of OTRs with skin cancer is complex
and requires longer appointment times, more frequent fol-
low-up, and a substantial amount of dermatologic surgical
procedures. Patients should be educated about this process.
Understandably, patients often become overwhelmed by the
numerous dermatologic surgical procedures. Among derma-
tologists, this is often referred to as “Mohs fatigue,” in which
patients may often ask for less-invasive procedures such as
electrodessication and curettage, even with the understand-
ing that these modalities are less effective, to avoid another
invasive procedure. Therefore in OTRs with cutaneous
malignancy, a specialty OTR dermatology clinic can be espe-
cially beneficial to prevent, diagnose, and manage the bur-
den of skin oncology in this patient population.50 
Immunosuppressive Drug
Cutaneous Side Effects
CORTICOSTEROIDS
Most transplant immunosuppression regimens include
corticosteroids, often early in the posttransplant course.
Cutaneous effects of corticosteroid use are well recognized
and include cushingoid effects: redistribution of body fat,
purpura, striae, telangiectasia, and thinning of the skin.51
Corticosteroids stimulate the pilosebaceous unit, possi-
bly through an androgen-mediated mechanism, and this
34 • Cutaneous Disease in Kidney Transplantation Patients 585
Fig. 34.3  Steroid acne with monomorphic inflamed lesions and few
comedones.
is responsible for the appearance of hirsutism and steroid
acne. Steroid acne resembles acne vulgaris, affecting only
androgen-dependent areas of skin bearing sebaceous glands
(i.e., face, chest, back, and upper arms), but with predomi-
nant monomorphic papulopustules and a paucity of open
comedones (blackheads) (Fig. 34.3). Steroid-induced acne
is dose-dependent. Treatment consists of decreasing the
glucocorticoid dose and a trial of topical therapies including
benzoyl peroxide, erythromycin, and clindamycin.52 Oral
therapies, including doxycycline and other oral antibiotics
similarly used for acne, spironolactone in nonchildbearing
women, and isotretinoin, may be required for more resis-
tant cases.53
AZATHIOPRINE
Cutaneous side effects of azathioprine are rarely reported.
Hair loss has been reported in 108 of 200 (54%) transplant
recipients examined, and it was concluded that diffuse alo-
pecia was due to azathioprine in several of these cases.51 In
addition, changes in hair color and texture were seen in 22%
of the study population (attributed to azathioprine-induced
diffuse alopecia).51 An erythema nodosum hypersensitivity
reaction has also been reported, but in patients receiving
azathioprine for inflammatory bowel disease, which may
have been a result of the underlying illness rather than a
direct effect of azathioprine.54 
CYCLOSPORINE
Cyclosporine has largely been replaced by more effective
and safer immunosuppressant medications. Furthermore,
the doses used today are lower than those historically used.
These trends have decreased the frequency of cutaneous
adverse effects, which tend to be dose-dependent. The most
common cyclosporine-induced mucocutaneous effects
are hypertrichosis (affecting up to 100% of those taking
this drug) and gingival hyperplasia (affecting 2%–81%).55
Hypertrichosis does not appear to be an androgen-mediated
side effect because cyclosporine-induced hypertrichosis is
not confined to androgen-dependent areas of skin and is
independent of sex hormone levels.55 Hypertrichosis is more
common the longer that transplant recipients are exposed
to cyclosporine.55 Gingival hyperplasia is more common
586 Kidney Transplantation: Principles and Practice
with increasing time posttransplantation and younger
transplant recipients exposed to cyclosporine.56 In addi-
tion, pilosebaceous lesions are also a common development
as cyclosporine may be partially eliminated through seba-
ceous glands.57 Clinical lesions include sebaceous hyperpla-
sia, epidermal cysts, keratosis pilaris, and more nonspecific
follicular eruptions.58 
MYCOPHENOLATE MOFETIL
Mycophenolate mofetil seems to have a low incidence of
skin side effects, with fewer side effects documented com-
pared with azathioprine.59 The most frequent side effect
related to mycophenolate mofetil is aphthous stomatitis,
which can present more severely in patients who are on
mycophenolate mofetil and mammalian target of rapamy-
cin (mTOR) inhibitors (sirolimus, everolimus).60 There is
increased susceptibility to herpes simplex and zoster and
cytomegalovirus (CMV) infections.59 
TACROLIMUS
Tacrolimus has few reported mucocutaneous side effects.61
In one study, where 15 transplant recipients were switched
from cyclosporine to tacrolimus, gingival hyperplasia
resolved in all patients within 1 year and hypertrichosis
resolved in all cases within 6 months.61 Alopecia has been
reported in transplant recipients taking tacrolimus, and
in one case series it occurred in 29% of kidney transplant
recipients when other potential causes of alopecia were
ruled out.62  ferentiating AK from SCC may be difficult, and a biopsy is
SIROLIMUS AND EVEROLIMUS
Cutaneous side effects in kidney transplant recipients receiv-
ing sirolimus may be severe and are well characterized.63
Aphthous ulceration is significantly associated with siroli-
mus therapy and was observed in 60% of patients.63 Aggres-
sive use of a potent topical steroid may aid in treatment of
these ulcers. Disorders of the pilosebaceous unit were fre-
quently observed, with acneiform eruptions being the most
common and observed in 46% of patients.63 Chronic edema
was seen in 55% and angioedema in 15%.63 Mucous mem-
brane pathologies were also very common.63 Alopecia of
the scalp was observed in 11% and hypertrichosis was seen
in 16%.63 During the 3-month period after completion of
the study, 12% of patients had to stop sirolimus secondary
to cutaneous effects, including hidradenitis suppurativa,
severe acne, severe limb edema, and nail disorders.63 
Premalignant and Benign
Cutaneous Tumors in Renal
Transplant Patients
ACTINIC KERATOSIS
Actinic keratoses (AKs) are precursor lesions of SCC. AKs
are among the most frequently encountered skin lesions in
clinical dermatology practice. They present on sun-dam-
aged skin of the head, neck, upper trunk, and extremities
Fig. 34.4  Seborrheic keratoses on the trunk of a male patient, illus-
trating the number and variation in shape, size, and color that may be
observed in these lesions.
(see Fig. 34.2). AK results in mild dysplasia in the epidermis
on histopathology. Clinically, AKs present as erythematous
scaling macules and papules. These may be very hyperkera-
totic scales, some with a cutaneous horn. The pathogenesis
of actinic keratosis is identical to SCC.
In the general population, the likelihood of an invasive
SCC evolving from a given AK has been estimated to occur
at a rate of 0.075 to 0.096% per lesion per year.4 This may
be higher in OTRs.
In OTRs, the actinic burden may be very high and dis-
tressing to the patient. From the clinical perspective, dif-
warranted for lesions not responding to traditional therapy
for actinic keratosis.
The mainstay of treatment for an isolated AK is cryo-
therapy. However, OTRs often have numerous AKs, render-
ing cryotherapy impractical. In particular, male Caucasian
OTRs often develop the “transplant scalp” which involves the
development of numerous AKs on the scalp.4 This increases
the likelihood of developing SCC with numerous lesions.
Also, this can make surgical margin control for SCC on the
scalp difficult. For transplant scalp, field treatment with a
topical therapy is recommended. Treatment options are sim-
ilar to those mentioned for NMSC including 5-­fluorouracil
cream, imiquimod, and photodynamic therapy.4 For par-
ticularly hyperkeratotic lesions, curettage may be necessary
before treatment. Sun protection should be advised. 
SEBORRHEIC KERATOSIS
Seborrheic keratoses (SKs) are common benign skin lesions
that are almost ubiquitous among older individuals. SKs
present as tan to brown, waxy, “stuck-on” appearing pap-
ules (Fig. 34.4). These may be more common in OTRs; how-
ever these may appear similarly to viral warts, which occur
more commonly in OTRs. SKs are also more prevalent in
lighter skinned, older patients who have been transplanted
the longest.64 SKs may become inflamed and be treated
with cryotherapy or curettage.
SKs are generally felt to be benign; however, if there is a
suspicious lesion in an OTR, this should be biopsied. A retro-
spective study of SCC arising in SKs demonstrated a higher
risk in OTRs.65 HPV testing was not done in this study.65 

POROKERATOSIS
Porokeratoses are benign skin lesions that may rarely have
malignant potential to develop SCC. These present as tan-
to-brown macules or thin plaques with central atrophy and
with a peripheral collarette of scale. Disseminated superfi-
cial actinic porokeratosis (DSAP) located on the extremi-
ties is often seen in OTRs with chronic ultraviolet exposure
history. The incidence of porokeratoses in OTRs, from two
population-based studies, is between 8% to 10.68%.66
Immunosuppression has been suggested to play a role
in the development of porokeratosis, and the incidence of
porokeratoses has been directly linked to strength of immu-
nosuppressive therapy.67 The risk of malignant transfor-
mation of porokeratosis to SCC in the general population is
approximately 7%, which may be greater in OTRs second-
ary to immunosuppression, larger lesion sizes, and config-
uration.67 Treatment is challenging and mostly cosmetic;
cryotherapy often leads to unwanted scarring. If required,
treatment can be approached through topical chemothera-
pies including 5-fluorouracil or imiquimod, photodynamic
therapy, and chemical peels.68 Sun protection should be
advised.  with duration from transplant75 (Fig. 34.5). These results
Infections and Inflammatory
Cutaneous Findings in OTRs
CUTANEOUS INFECTIONS
Overall, the most frequently encountered cutaneous infec-
tions in transplant recipients are superficial fungal infec-
tions and viral warts.
Viral Infections
Given the suppression of T cell immunity and the role of
T lymphocytes in combating viral pathogens, viral infec-
tions tend to predominate 1 to 6 months posttransplanta-
tion.69 Antiviral prophylaxis has significantly decreased the
incidence of herpes virus (HHV) infections that historically
occurred between 1 and 6 months posttransplantation.70,71
However, reactivation of HHV represents a significant risk in
this patient population and is important to diagnose and treat.
The most common HHV infections in OTRs are herpes sim-
plex viruses (HSV types 1 and 2); varicella zoster virus (VZV);
cytomegalovirus; Epstein-Barr virus; and HHV-6, HHV-7,
and HHV-8, which is the causative agent of KS.72 HSV infec-
tion is most commonly manifested through mucocutaneous
lesions in OTRs and must be distinguished between siroli-
mus-induced mucositis in certain patients.72 The risk of HSV
infection decreases 6 months after transplantation as immu-
nosuppression is tapered. However, when lesions develop,
they can be painful, persistent, and rarely disseminate to dis-
tant organs.73 The most common treatments are acyclovir
and valacyclovir, which can be used acutely and as suppres-
sive therapy. If VZV infection disseminates in a transplant
patient, intravenous acyclovir is the preferred treatment.
After the sixth postoperative month, OTRs continue to be
at high risk for developing community-acquired infections,
and over time more indolent infections begin to develop,
which are frequently caused by HPVs.69,74 In a prevalence
study of renal transplant recipients, the most common
34 • Cutaneous Disease in Kidney Transplantation Patients 587
Fig. 34.5  Extensive common warts on the hands of a kidney transplant
recipient.
cutaneous infection was viral warts, which was found in
38% of patients and increased in frequency in concordance
were consistent with several previous studies.75
The severity of cutaneous warts may be pronounced
in immunosuppressed patients (see Fig. 34.5). Acquired
epidermodysplasia verruciformis (EV), which is a specific
pathology finding and suggests an increased susceptibility
to HPV infection, has been reported in immunocompro-
mised patients.76 There may be an association with wors-
ening disease with azathioprine; however, this requires
further study.76
HPV infections in OTRs can be challenging to treat and
are an additional risk factor for NMSC, especially in this
patient population.77 Treatment can either be attempted
through physical destruction (cryotherapy, curettage,
laser) or topical therapies including salicylic acid, podophyl-
lum, cantharidin, trichloroacetic acid, topical cidofovir,
topical vitamin D, retinoids, 5-floururacil, or imiquimod.72
Even with clearance, viral warts are a chronic condition,
and recurrence should be anticipated.
Less frequently, molluscum contagiosum (MC), a pox-
virus that infects squamous epithelia, has been shown to
occur in nearly 7% of pediatric OTRs and extensively in
immunocompromised patients including OTRs.78,79 MC
can be treated by surgically removing the umbilicated core,
cryoablation, electrodessication, cantharidin, trichloroace-
tic acid, podophyllum, and topical tretinoin.72 Other rare
viral infections include viral-associated trichodysplasia spi-
nulosa and acquired epidermodysplasia verruciformis.80,81 
Fungal Infections
Cutaneous fungal infections also occur frequently because
of the suppression of cell-mediated immunity. In the early
posttransplantation period, when immunosuppression is
greatest, disseminated candidiasis and aspergillosis, both
primary cutaneous and secondary cutaneous resulting
from invasive disease, are frequently seen, but with insti-
tutional variability in incidence. Immunosuppressive doses
also tend to be high 1 to 6 months posttransplantation and
patients continue to be at significant risk of developing
an opportunistic deep fungal infection. Common mycoses
588 Kidney Transplantation: Principles and Practice
Fig. 34.6  Pityriasis versicolor: pigmented macular lesions with superfi-
cial scaling over the shoulder region.
include dimorphic fungi infections, zygomycoses, phaeohy-
phomycosis, hyalohyphomycosis, cryptococcosis, and con-
tinued risk from Candida and Aspergillus. Skin lesions range
from nonerythematous papules, erythematous macules,
papules and nodules (+/− necrosis), hemorrhagic bullae,
abscesses, and cellulitis. Cutaneous fungal infections may
occur in isolation or be a clue to underlying systemic infec-
tion. Early recognition of systemic infection is imperative
given the potential mortality associated with disseminated
disease.82 As clinical presentation is variable and relatively
nonspecific, a high index of suspicion and early biopsies of
skin lesions for histologic examination and culture are criti-
cal for diagnosis. Therapy usually requires systemic anti-
fungal compounds including triazoles of voriconazole and
posaconazole, amphotericin B, and echinocandins such as
caspofungin, micafungin, and anidulafungin, but surgi-
cal debridement/excision may be an adjunct in localized
disease.82
Overall, superficial fungal infections are more common
infections in OTRs. Mucocutaneous candidiasis is frequent,
especially early in posttransplantation.83 Nystatin or topi-
cal azoles are commonly used and are effective treatments
for superficial candida infections. Dermatophyte infections
often present atypically because of a lack of erythema that
is normally produced by local inflammation.84 Pityriasis
versicolor has been identified as the most common fungal
infection in OTRs in several studies and can be treated with
topical or oral medications, most commonly topical azole
antifungals85 (Fig. 34.6). Other frequent infections include
chronic tinea pedis and onychomycosis, both of which are
more common with chronic immunosuppression85 (Fig.
34.7). Oral terbinafine is the treatment of choice and has
the benefit of little interaction with immunosuppressants,
but liver function should be monitored during therapy.  4. Otley CC, Staskp T. Skin disease in organ transplantation. New York:
Common Inflammatory Disorders
Although several of the inflammatory dermatoses encoun-
tered in OTRs are due to drug effects, several conditions
arise from an immunosuppressed state or hypersensitiv-
ity reaction, including folliculitis (which may be bacterial
or fungal or viral), drug rash, keratosis pilaris, hair loss of
telogen effluvium-type, sebaceous hyperplasia, seborrheic
Fig. 34.7  Fungal nail infection (onychomycosis) affecting toenails.
dermatitis (SD), acrochordons, porokeratosis, and sebor-
rheic warts.64,86
In particular, SD in transplant recipients may be severe
and require treatment. SD has been reported to occur in
9.5% of renal transplant recipients, which is much higher
than SD prevalence of 1% to 5% reported in the normal
adult population.86 Although the precise etiology of SD is
unclear, the impaired T cell immunity in OTRs may lead to
an altered immune response to Malassezia species and more
prevalent SD.86 Treatment with combination topical anti-
fungals, steroids, or calcineurin inhibitors remain effective
therapies for SD in OTR.86 
Conclusion
OTRs suffer from a higher burden of malignant, infectious,
inflammatory, and benign skin disease than the general
population. In particular, the risk of NMSC in OTRs war-
rants multidisciplinary care between a patient’s trans-
plant physician and a dermatologist. Patient education of
increased risk of cutaneous malignancy and the impor-
tance of prevention are of the utmost importance in the care
of OTRs.
References
1. Zwald FO, Brown M. Skin cancer in solid organ transplant recipi-
ents: advances in therapy and management: part I. Epidemiology of
skin cancer in solid organ transplant recipients. J Am Acad Dermatol
2011;65:253–61. Quiz 62.
2. Garrett GL, Blanc PD, Boscardin J, et al. Incidence of and risk factors
for skin cancer in organ transplant recipients in the United States.
JAMA Dermatol 2017;153:296–303.
3. Urwin HR, Jones PW, Harden PN, et al. Predicting risk of nonmela-
noma skin cancer and premalignant skin lesions in renal transplant
recipients. Transplantation 2009;87:1667–71.
Cambridge University Press; 2008.
5. Arron ST, Jennings L, Nindl I, et al. Viral oncogenesis and its role in
nonmelanoma skin cancer. Br J Dermatol 2011;164:1201–13.
6. Genders RE, Mazlom H, Michel A, et al. The presence of betapapillo-
mavirus antibodies around transplantation predicts the development
of keratinocyte carcinoma in organ transplant recipients: a cohort
study. J Invest Dermatol 2015;135:1275–82.
7. Chung CL, Nadhan KS, Shaver CM, et al. Comparison of posttrans-
plant dermatologic diseases by race. JAMA Dermatol 2017;153(6):
552–8.
8. Vinzon SE, Braspenning-Wesch I, Muller M, et al. Protective vaccina-
tion against papillomavirus-induced skin tumors under immunocom-

petent and immunosuppressive conditions: a preclinical study using a
natural outbred animal model. PLoS Pathog 2014;10:e1003924.
9. Winkelhorst JT, Brokelman WJ, Tiggeler RG, Wobbes T. Incidence and
clinical course of de-novo malignancies in renal allograft recipients.
Eur J Surg Oncol 2001;27:409–13.
10. Sheil AG, Disney AP, Mathew TH, Amiss N. De novo malignancy
emerges as a major cause of morbidity and late failure in renal trans-
plantation. Transplant Proc 1993;25:1383–4.
11. Humphreys TR, Shah K, Wysong A, Lexa F, MacFarlane D. The role
of imaging in the management of patients with nonmelanoma skin
cancer: when is imaging necessary? J Am Acad Dermatol 2017;
76:591–607.
12. Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin
cancer and reduction of keratotic skin lesions during acitretin ther-
apy in renal transplant recipients: a double-blind, placebo-controlled
study. J Clin Oncol 1995;13:1933–8.
13. Kovach BT, Sams HH, Stasko T. Systemic strategies for chemopre-
vention of skin cancers in transplant recipients. Clin Transplant
2005;19:726–34.
14. Zwald FO, Brown M. Skin cancer in solid organ transplant recipients:
advances in therapy and management: part II. Management of skin
cancer in solid organ transplant recipients. J Am Acad Dermatol
2011;65:263–79. Quiz 80.
15. Jirakulaporn T, Endrizzi B, Lindgren B, Mathew J, Lee PK, Dudek AZ.
Capecitabine for skin cancer prevention in solid organ transplant
recipients. Clin Transplant 2011;25:541–8.
16. Chen AC, Martin AJ, Choy B, et  al. A phase 3 randomized trial
of nicotinamide for skin-cancer chemoprevention. N Engl J Med
2015;373:1618–26.
17. Jenni D, Karpova MB, Muhleisen B, et al. A prospective clinical trial
to assess lapatinib effects on cutaneous squamous cell carcinoma and
actinic keratosis. ESMO Open 2016;1:e000003.
18. Siano M, Molinari F, Martin V, et  al. Multicenter phase II study of
panitumumab in platinum pretreated, advanced head and neck squa-
mous cell cancer. Oncologist 2017;22(7). 782-70.
19. Degache E, Crochet J, Simon N, et  al. Major response to pembroli-
zumab in two patients with locally advanced cutaneous squamous
cell carcinoma. J Eur Acad Dermatol Venereol 2018;32(7):e257–8.
20. Taylor P. Regeneron and Sanofi bag breakthrough status for PD-1
latecomer. Fierce Biotech website 2017. Available online at: http://
www.fiercebiotech.com/biotech/regeneron-and-sanofi-bag-break-
through-status-for-pd-1-latecomer. Accessed September 21, 2017.
21. Sekulic A, Migden MR, Basset-Seguin N, et al. Long-term safety and
efficacy of vismodegib in patients with advanced basal cell carci-
noma: final update of the pivotal ERIVANCE BCC study. BMC Cancer
2017;17:332.
22. Mohan SV, Chang J, Li S, Henry AS, Wood DJ, Chang AL. Increased
risk of cutaneous squamous cell carcinoma after vismodegib therapy
for basal cell carcinoma. JAMA Dermatol 2016;152:527–32.
23. Bhutani T, Abrouk M, Sima CS, et al. Risk of cutaneous squamous cell
carcinoma after treatment of basal cell carcinoma with vismodegib.
J Am Acad Dermatol 2017;77(4):713–8.
24. Zwald F, Leitenberger J, Zeitouni N, et  al. Recommendations for solid
organ transplantation for transplant candidates with a pretransplant
diagnosis of cutaneous squamous cell carcinoma, Merkel cell carcinoma
and melanoma: a consensus opinion from the International Transplant
Skin Cancer Collaborative (ITSCC). Am J Transplant 2016;16:407–13.
25. Arron ST, Raymond AK, Yanik EL, et  al. Melanoma outcomes in
transplant recipients with pretransplant melanoma. Dermatol Surg
2016;42:157–66.
26. Zwald FO, Christenson LJ, Billingsley EM, et  al. Melanoma in solid
organ transplant recipients. Am J Transplant 2010;10:1297–304.
27. Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Leng-
erich EJ. Increased incidence of melanoma in renal transplantation
recipients. Cancer 2005;104:1962–7.
28. Ascha M, Ascha MS, Tanenbaum J, Bordeaux JS. Risk factors
for melanoma in renal transplant recipients. JAMA Dermatol
2017;153:1130–6.
29. Brewer JD, Christenson LJ, Weaver AL, et al. Malignant melanoma in
solid transplant recipients: collection of database cases and compari-
son with surveillance, epidemiology, and end results data for outcome
analysis. Arch Dermatol 2011;147:790–6.
30. Milton CA, Barbara J, Cooper J, Rao M, Russell C, Russ G. The trans-
mission of donor-derived malignant melanoma to a renal allograft
recipient. Clin Transplant 2006;20:547–50.
34 • Cutaneous Disease in Kidney Transplantation Patients 589
31. Markovic SN, Erickson LA, Rao RD, et al. Malignant melanoma in the
21st century, part 1: epidemiology, risk factors, screening, preven-
tion, and diagnosis. Mayo Clin Proc 2007;82:364–80.
32. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or
nodal observation in melanoma. N Engl J Med 2006;355:1307–17.
33. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or
observation for sentinel-node metastasis in melanoma. N Engl J Med
2017;376:2211–22.
34. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival
in melanoma with combined dabrafenib and trametinib. N Engl J Med
2015;372:30–9.
35. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilim-
umab in advanced melanoma. N Engl J Med 2015;372:2521–32.
36. Arron ST, Canavan T, Yu SS. Organ transplant recipients with Merkel
cell carcinoma have reduced progression-free, overall, and disease-
specific survival independent of stage at presentation. J Am Acad Der-
matol 2014;71:684–90.
37. Garrett GL, Zargham H, Schulman JM, Jafarian F, Yu SS, Arron ST.
Merkel cell carcinoma in organ transplant recipients: case reports and
review of the literature. JAAD Case Rep 2015;1:S29–32.
38. Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 Blockade with pembrolizumab
in advanced Merkel-cell carcinoma. N Engl J Med 2016;374:2542–52.
39. McCoppin HH, Christiansen D, Stasko T, et  al. Clinical spectrum of
atypical fibroxanthoma and undifferentiated pleomorphic sarcoma
in solid organ transplant recipients: a collective experience. Dermatol
Surg 2012;38:230–9.
40. Chiereghin A, Barozzi P, Petrisli E, et al. Multicenter prospective study
for laboratory diagnosis of HHV8 infection in solid organ donors and
transplant recipients and evaluation of the clinical impact after trans-
plantation. Transplantation 2017;101:1935–44.
41. Karia PS, Azzi JR, Heher EC, Hills VM, Schmults CD. Association of
sirolimus use with risk for skin cancer in a mixed-organ cohort of
solid-organ transplant recipients with a history of cancer. JAMA Der-
matol 2016;152:533–40.
42. Lim WH, Russ GR, Wong G, Pilmore H, Kanellis J, Chadban SJ. The
risk of cancer in kidney transplant recipients may be reduced in those
maintained on everolimus and reduced cyclosporine. Kidney Int
2017;91:954–63.
43. Asgari MM, Arron ST, Warton EM, Quesenberry CP, Weisshaar D.
Sirolimus use and risk of cutaneous squamous cell carcinoma (SCC)
in solid organ transplant recipients (SOTRs). J Am Acad Dermatol
2015;73:444–50.
44. Cowen EW, Nguyen JC, Miller DD, et  al. Chronic phototoxicity and
aggressive squamous cell carcinoma of the skin in children and
adults during treatment with voriconazole. J Am Acad Dermatol
2010;62:31–7.
45. Clancy CJ, Nguyen MH. Long-term voriconazole and skin cancer: is
there cause for concern? Curr Infect Dis Rep 2011;13:536–43.
46. Singer JP, Boker A, Metchnikoff C, et al. High cumulative dose expo-
sure to voriconazole is associated with cutaneous squamous cell
carcinoma in lung transplant recipients. J Heart Lung Transplant
2012;31:694–9.
47. Mansh M, Binstock M, Williams K, et al. Voriconazole exposure and
risk of cutaneous squamous cell carcinoma, aspergillus colonization,
invasive aspergillosis and death in lung transplant recipients. Am J
Transplant 2016;16:262–70.
48. Zwald FO, Spratt M, Lemos BD, et al. Duration of voriconazole expo-
sure: an independent risk factor for skin cancer after lung transplanta-
tion. Dermatol Surg 2012;38:1369–74.
49. Ibrahim SF, Singer JP, Arron ST. Catastrophic squamous cell carci-
noma in lung transplant patients treated with voriconazole. Dermatol
Surg 2010;36:1752–5.
50. Ismail F, Mitchell L, Casabonne D, et al. Specialist dermatology clinics
for organ transplant recipients significantly improve compliance with
photoprotection and levels of skin cancer awareness. Br J Dermatol
2006;155:916–25.
51. Koranda FC, Dehmel EM, Kahn G, Penn I. Cutaneous complica-
tions in immunosuppressed renal homograft recipients. JAMA
1974;229:419–24.
52. Dessinioti C, Antoniou C, Katsambas A. Acneiform eruptions. Clin
Dermatol 2014;32:24–34.
53. Ponticelli C, Bencini PL. Nonneoplastic mucocutaneous lesions in
organ transplant recipients. Transpl Int 2011;24:1041–50.
54. de Fonclare AL, Khosrotehrani K, Aractingi S, Duriez P, Cosnes J,
Beaugerie L. Erythema nodosum-like eruption as a manifestation of
590 Kidney Transplantation: Principles and Practice
azathioprine hypersensitivity in patients with inflammatory bowel
disease. Arch Dermatol 2007;143:744–8.
55. Lindholm A, Pousette A, Carlstrom K, Klintmalm G. Ciclosporin-­
associated hypertrichosis is not related to sex hormone levels follow-
ing renal transplantation. Nephron 1988;50:199–204.
56. Daley TD, Wysocki GP, Day C. Clinical and pharmacologic correla-
tions in cyclosporine-induced gingival hyperplasia. Oral Surg Oral
Med Oral Pathol 1986;62:417–21.
57. Heaphy Jr MR, Shamma HN, Hickmann M, White MJ. Cyclosporine-
induced folliculodystrophy. J Am Acad Dermatol 2004;50:310–5.
58. Bencini PL, Montagnino G, Sala F, De Vecchi A, Crosti C, Tarantino A.
Cutaneous lesions in 67 cyclosporin-treated renal transplant recipi-
ents. Dermatologica 1986;172:24–30.
59. Wang K, Zhang H, Li Y, et al. Safety of mycophenolate mofetil versus
azathioprine in renal transplantation: a systematic review. Trans-
plant Proc 2004;36:2068–70.
60. Campistol JM, de Fijter JW, Flechner SM, Langone A, Morelon E,
Stockfleth E. mTOR inhibitor-associated dermatologic and mucosal
problems. Clin Transplant 2010;24:149–56.
61. Busque S, Demers P, Saint-Louis G, et al. Hypertrichosis and gingival
hypertrophy regression in renal transplants following the substitution
of cyclosporin by tacrolimus. Ann Chir 1999;53:687–9.
62. Tricot L, Lebbe C, Pillebout E, Martinez F, Legendre C, Thervet E.
Tacrolimus-induced alopecia in female kidney-pancreas transplant
recipients. Transplantation 2005;80:1546–9.
63. Mahe E, Morelon E, Lechaton S, et  al. Cutaneous adverse events in
renal transplant recipients receiving sirolimus-based therapy. Trans-
plantation 2005;79:476–82.
64. Lally A, Casabonne D, Waterboer T, et al. Association of seborrhoeic
warts with skin cancer in renal transplant recipients. J Eur Acad Der-
matol Venereol 2010;24:302–7.
65. Conic RZ, Napekoski K, Schuetz H, Piliang M, Bergfeld W, Atanas-
kova Mesinkovska N. The role of immunosuppression in squamous
cell carcinomas arising in seborrheic keratosis. J Am Acad Dermatol
2017;76:1146–50.
66. Herranz P, Pizarro A, De Lucas R, et al. High incidence of porokerato-
sis in renal transplant recipients. Br J Dermatol 1997;136:176–9.
67. Zenarola P, Melillo L, Lomuto M, Carotenuto M, Gomes VE,
Marzocchi W. Exacerbation of porokeratosis: a sign of immunodepres-
sion. J Am Acad Dermatol 1993;29:1035–6.
68. Stoff B, Salisbury C, Parker D, O’Reilly Zwald F. Dermatopathology
of skin cancer in solid organ transplant recipients. Transplant Rev
(Orlando) 2010;24:172–89.
69. Fishman JA. Infection in solid-organ transplant recipients. N Engl J
Med 2007;357:2601–14.
70. Rubin RH, Kemmerly SA, Conti D, et al. Prevention of primary cyto-
megalovirus disease in organ transplant recipients with oral ganciclo-
vir or oral acyclovir prophylaxis. Transpl Infect Dis 2000;2:112–7.
71. Meyers JD, Wade JC, Mitchell CD, et  al. Multicenter collaborative
trial of intravenous acyclovir for treatment of mucocutaneous herpes
simplex virus infection in the immunocompromised host. Am J Med
1982;73:229–35.
72. Tan HH, Goh CL. Viral infections affecting the skin in organ transplant
recipients: epidemiology and current management strategies. Am J
Clin Dermatol 2006;7:13–29.
73. Smith SR, Butterly DW, Alexander BD, Greenberg A. Viral infections
after renal transplantation. Am J Kidney Dis 2001;37:659–76.
74. Berkhout RJ, Bouwes Bavinck JN, ter Schegget J. Persistence of
human papillomavirus DNA in benign and (pre)malignant skin
lesions from renal transplant recipients. J Clin Microbiol 2000;
38:2087–96.
75. Rudlinger R, Smith IW, Bunney MH, Hunter JA. Human papillomavi-
rus infections in a group of renal transplant recipients. Br J Dermatol
1986;115:681–92.
76. Ovits CG, Amin BD, Halverstam C. Acquired epidermodysplasia
verruciformis and its relationship to immunosuppressive therapy:
report of a case and review of the literature. J Drugs Dermatol
2017;16:701–4.
77. Benton EC, McLaren K, Barr BB, et al. Human papilloma virus infec-
tion and its relationship to skin cancer in a group of renal allograft
recipients. Curr Probl Dermatol 1989;18:168–77.
78. Euvrard S, Kanitakis J, Cochat P, Cambazard F, Claudy A. Skin dis-
eases in children with organ transplants. J Am Acad Dermatol
2001;44:932–9.
79. Mansur AT, Goktay F, Gunduz S, Serdar ZA. Multiple giant mollus-
cum contagiosum in a renal transplant recipient. Transpl Infect Dis
2004;6:120–3.
80. Henley JK, Hossler EW. Acquired epidermodysplasia verruciformis
occurring in a renal transplant recipient. Cutis 2017;99:E9–12.
81. Sperling LC, Tomaszewski MM, Thomas DA. Viral-associated tricho-
dysplasia in patients who are immunocompromised. J Am Acad Der-
matol 2004;50:318–22.
82. Virgili A, Zampino MR, Mantovani L. Fungal skin infections in organ
transplant recipients. Am J Clin Dermatol 2002;3:19–35.
83. Ribeiro PM, Bacal F, Koga-Ito CY, Junqueira JC, Jorge AO. Presence
of Candida spp. in the oral cavity of heart transplantation patients.
J Appl Oral Sci 2011;19:6–10.
84. Miele PS, Levy CS, Smith MA, et al. Primary cutaneous fungal infec-
tions in solid organ transplantation: a case series. Am J Transplant
2002;2:678–83.
85. Shuttleworth D, Philpot CM, Salaman JR. Cutaneous fungal infection
following renal transplantation: a case control study. Br J Dermatol
1987;117:585–90.
86. Lally A, Casabonne D, Newton R, Wojnarowska F. Seborrheic derma-
titis among Oxford renal transplant recipients. J Eur Acad Dermatol
Venereol 2010;24:561–4.