Khối U Ác Tính Dưới Da: Góc Nhìn Phẫu Thuật (Cutaneous Malignancies)

between UV irradiation and infection. However, the particularly
high-risk serotypes of HPV are not always found in SCC lesions.
These HPV serotypes express proteins that inactivate the tumor
suppressors p53 and Rb, but SCCs often have direct mutations
in p53 and Rb pathway components, obviating a need for the
virally expressed proteins.45
The exact contributions of
decreased tumor surveillance, unchecked viral oncogenesis, or
both to the increased incidence of nonmelanoma skin cancer in
immunocompromised patients remain to be determined.
Further evidence of a viral contribution to skin cancer in
immunosuppressed patients can be found from Merkel cell car-
cinoma (MCC). This rare, very aggressive neuroendocrine tumor
of the skin is associated with Merkel cell polyomavirus (MCV).
Immunocompromised patients are 15 times more likely to
develop MCC than their immunocompetent counterparts and
they are diagnosed with the malignancy an average of 10 years
earlier.46 As with nonmelanoma skin cancer, MCC is more
aggressive in immunocompromised patients with 56% of
patients succumbing to their disease in one study with a mean
time from diagnosis to death of only 13 months.47
12.5 Mechanisms of Immunosup-
pression and Association with
Cutaneous Malignancies
12.5.1 Human Immunodeficiency Virus
HIV is the leading cause of acquired immunodeficiency in the
world with an estimated 35 million people infected as of 2013
(World Health Organization). HIV attacks CD4+ T cells, the
helper T cells that orchestrate immune responses to pathogens
and also coordinate tumor surveillance. Untreated, HIV depletes
the body of this vital cell population. When CD4+ T cell counts
fall su ciently, a host of attendant illnesses and opportunistic
infections occur. These define the AIDS.
The link between HIV infection and cutaneous malignancy is
longstanding. The emergence of KS in immunosuppressed
homosexual men in the early 1980s led to KS being among the
original AIDS-defining illnesses. KS is associated with human
herpes virus 8 (HHV8), with nearly all patients exhibiting viral
DNA in tumor samples.48,49,50,51
The inverse relationship
between KS and CD4+ cell counts provides powerful evidence
that the immune system can suppress this malignancy. Consis-
tent with this, the incidence of KS has declined dramatically
since the advent of combination antiretroviral therapy (cART),
which preserves functional CD4+ levels.52 Further, initiation of
cART has been shown to decrease KS lesion size and number
and represents a critical component of treatment.53,54
Nonmelanoma skin cancers are the most frequent non-AIDS-
defining cancers in HIV+ patients.55 In a large, retrospective
study of over 4,000 HIV-infected patients followed between
1988 and 2003, 32% of all malignancies were BCC and 16% were
SCC. Patients who have progressed to AIDS have a threefold to
fivefold higher risk of developing nonmelanoma skin cancers.56,
57 The high incidence of nonmelanoma skin cancers in HIV+
patients may not be surprising since these are also the most
common cancers in the general population. However, other
characteristics of these tumors may di er in HIV+ patients. One
study from the University of California, San Francisco, found ear-
lier age of onset, higher risk of local recurrence and metastasis,
and a higher lethality of SCCs in patients with HIV. Interestingly,
BCC is found more frequently than SCC in the HIV+ patient popu-
lation, mirroring the distribution of these tumors in the general
populace. As discussed below, this is in contrast to transplant
patients who show a relative propensity of SCC. Whether this
reflects di erences in virally versus chemically mediated immu-
nosuppression or other factors remains to be seen.
The aggressive nature of SCC in HIV+ patients necessitates
vigilance and aggressive management. Wilkins and colleagues
recommend early biopsy of suspicious cutaneous lesions along
with frequent monitoring for possible recurrence or metasta-
sis.58 These patients should be considered for sentinel node
mapping for tumors presenting with an aggressive clinical pre-
sentation. These include recurrent lesions, tumors with depth
of invasion more than 2 mm, tumors that exhibit perineural or
lymphatic/vascular invasion, and poorly di erentiated tumors.
Tumors more than 2 cm in diameter on the trunk and 0.6 cm on
the “mask” areas of the face, genitalia, hands, and feet are more
likely to behave aggressively as well. Adjunctive therapies such
as chemotherapy or radiation may also be considered.58
Patients with BCC should be treated in the standard fashion
with wide local excision.58
Melanoma—already the most aggressive of common cutane-
ous malignancies—is even more lethal in patients with HIV. In a
case control study of HIV+ and HIV– patients with melanomas of
the same subtype and thickness, outcomes were significantly
worse in patients with HIV.59 Both disease-free survival and
overall survival were reduced among HIV+ patients. Further, the
time to melanoma recurrence in treated patients was inversely
related to CD4+ counts. This fact coupled with the recent suc-
cess of immunostimulatory medications in treating advanced
melanoma suggests that the immune system may play an
important role in controlling this malignancy even in immu-
nocompetent people. Management of melanoma in patients
with HIV should follow standard treatment protocols with an
emphasis on restoring or preserving immune function
through cART. Use of new immunostimulatory medications
for melanoma treatment in HIV+ patients is a promising area
for the future.
12.6 Organ Transplantation
The development of e ective immunosuppressive medications
in the 1980s enabled an enormous increase in lifesaving organ
transplantation. The need for replacement organs greatly out-
strips supply with over 123,000 patients on waiting lists in the
United States (Organ Procurement and Transplantation Net-
work) and the gap continues to widen. Nearly 30,000 organ
transplants were performed in the United States in 2013
(organdonor.gov). Further advances in immunosuppressive reg-
imens, surgical technique, and posttransplant care have
increased life expectancies for transplant recipients. Five-year
survival approaches 85% for kidney transplant recipients, 48%
for lung transplant, and 70% for liver and heart transplant.60
These advances have led to a large number of patients living
long term with organ transplants. An estimated 140,000 trans-
plant recipients live in the United States currently.60
High-Risk Cutaneous Malignancies
238

The requirement for lifelong imm unosuppression to pre-
vent transplant rejection leaves these patients in a state of
chronic im mune deficiency. The deleterious consequences of
transplant-associated im munosuppression include cardiovas-
cular disease, heightened susceptibility to infections, and
increased incidence of m alignancies. Studies across trans-
plant registry cohorts have revealed a twofold to fourfold
increased risk of developing cancer in transplant patients
relative to m atched controls.17 A recent study exam ined
m ore than 175,000 transplant recipients in the United States
over an 11-year period, considering data from transplant
and cancer registries.17 These patients had twice the risk of
developing m alignancies compared to the general popula-
tion. The risk of developing cutaneous m alignancies is par-
ticularly elevated am ong transplant patients w ith an
estim ated cumulative risk as high as 70%.61,62,63 This m akes
cutaneous malignancy the most frequently encountered can-
cer type in transplant recipients. These cancers include SCC,
BCC, KS, MCC, and cutaneous lymphom a.64
12.6.1 Biology
Cutaneous malignancies are not only more frequent in organ
transplant recipients, but also exhibit a more aggressive course
(Fig. 12.1). Data from the Cincinnati Transplant Registry dem-
onstrate that 5% of transplant patients with cutaneous malig-
nancies ultimately succumb to these tumors compared with 1
to 2% of patients who had not been transplanted.65 In kidney
transplant patients, 13% of patients exhibit SCC recurrence in
the 6 months following excision.61 Patients with metastatic
cutaneous malignancies have overall and disease-free survivals
at 3 years of only 48% and 56%, respectively.66
The increased aggressiveness of cutaneous m alignancies in
transplant patients m ay be explained by alterations in tumor
biology, impaired antitum or responses, or both. Evidence for
the form er com es from the observation that m atrix metallo-
proteinase expression is elevated in SCCs from transplant
recipients.67,68
These proteins degrade the extracellular
m atrix and may thereby provide a path for local invasion
and ultimate metastasis. Interestingly, alterations in the
matrix m etalloproteinase (MMP) profile are also found in
surrounding nonm alignant skin of transplant recipients. This
finding may play a role in the “field cancerization” that con-
tributes to the high ultim ate lesional burden in these
patients. It is also likely that impaired tumor surveillance
and antitum or im mune response allow incipient cutaneous
m alignancies to grow relatively unchecked. When combined
with the direct carcinogenic role of som e imm unosuppres-
sive medications, this decrease in antitumor response and
increase in MMP activity create a vicious cycle that pro-
m otes carcinogenesis.
12.6.2 Epidemiology
Nonmelanoma skin cancers including SCC and BCC are the most
frequent cutaneous malignancies in transplant patients,
accounting for 95% of observed tumors.60,69 Unlike the general
population, transplant recipients have a preponderance of SCC
over BCC in a 4:1 ratio. Interestingly, this represents an inver-
sion of the usual findings.70,71,72,73 The risk of developing SCC is
elevated 65-fold and the risk of BCC is elevated 10-fold relative
to the general population.74 As in the general population, these
cancers tend to occur in sun-exposed regions such as the head
and neck and upper extremities.74 Other markers of UV-associ-
ated skin damage such as actinic keratoses are associated with
an increased risk of nonmelanoma skin cancer in transplant
recipients.75 Interestingly, heart and lung transplant recipients
have a higher overall risk of SCC development than do kidney
transplant recipients, likely reflecting the more potent immu-
nosuppressive regimens required for organ preservation in the
former group.60
Melanom a risk is also elevated in organ transplant recipi-
ents. A threefold to fivefold increased risk of m elanoma is
present compared to the general population. These lesions
occur w ith a m ean duration of 5 years posttransplant.60 In a
study of nearly 90,000 transplant recipients over a 10-year
period, Hollenbeak and colleagues found an incidence of
m elanom a of 55.9 cases per 100,000 individuals on an age-
adjusted basis, w hich corresponds to a 3.6-fold greater risk
compared to the general population.76 Strikingly, among
Fig. 12.1 Multifocal cutaneous malignancies in a transplant patient. This patient developed multiple aggressive squamous cell carcinoma (SCCs) of the
face and hand after prolonged immunosuppression. (a) SCCs on the face. (b) SCC on the hand.
High-Risk Cutaneous Malignancies
239

African-Am erican kidney transplant recipients, the risk was
17.2-fold higher than in race-m atched healthy counterparts.
The rem arkable success of im munostim ulatory drugs in
combating m etastatic m elanoma—a success all the more
notable for the dism al natural history previously—points to
an important interplay between the im mune system and
m alignant m elanocytes. Interestingly, oncogenic BRAF m uta-
tions appear less com m only in melanom as of transplant
recipients.77 This suggests that im munosuppressive medica-
tions may activate alternative pathways to prom ote melano-
m agenesis or that impaired im m une surveillance abrogates
the need for this oncogenic pathway.77
Other cutaneous malignancies are also found more com-
monly in transplant recipients. KS incidence in these patients
occurs 84-fold to 500-fold more commonly, reflecting the
extreme rarity of the tumor in immunocompetent people.61,62,
78 This lesion is more common among men and is found in
regions of high HHV-8 seroprevalence including the Middle
East and Central and Southern Africa.79 MCC is found fivefold to
10-fold more frequently in organ transplant recipients, though
the rarity of this malignancy overall makes reliable data di cult
to obtain.80,81 As is the case in immunocompetent people, MCC
in transplant recipients is extremely aggressive. In a study of 41
solid organ transplant recipients who acquired MCC, the mean
duration from transplantation to development of MCC was 7 to
8 years.47 These tumors ultimately caused death in 56% of
patients despite a mean follow-up period of only 18 months in
the study.
The spectrum of cutaneous malignancies in transplant
patients closely parallels that of patients infected with HIV.11 A
notable exception is the higher ratio of SCC to BCC, which is not
found among HIV patients or among the general populace.
Whether this reflects alterations in the etiology of these non-
melanoma skin cancers by immunosuppressive drugs is an
important area for future investigation.
12.6.3 Demographics
Incidence of cutaneous malignancies is positively correlated
with the time since transplantation. In a study of transplant
patients in the Netherlands, cumulative incidence of cutaneous
malignancies increased from 10% at 10 years posttransplant to
40% after 20 years.73 In the United States and Europe, SCC risk
climbs from 10 to 27% at 10 years to 40 to 60% at 20 years.60
Patients in Australia have a striking 80% incidence at 20 years.60
The increased risk of skin cancer with time likely reflects the
duration of immunosuppression as well as greater exposure to
environmental carcinogens such as UV light.
Other characteristics that correlate with increased risk of
cutaneous malignancy in transplant patients include male gen-
der and older age.82,83 Compared to the general population,
however, skin cancers occur at a younger age in transplant
recipients. Cutaneous malignancies are the second most fre-
quently encountered cancers in pediatric transplant patients,
following posttransplantation lymphoproliferative disorder
(PTLD). These tumors typically manifest in young adulthood,
with an average age of onset of 27 years.84 Melanoma accounts
for a proportionally higher percentage of skin cancers in pedia-
tric transplant patients compared to adults.85
12.6.4 Risk Factors
Risk factors for developing cutaneous malignancies in trans-
plant recipients parallel those in the general populace. History
of a previous cutaneous malignancy places an individual at
higher risk of acquiring another following organ transplanta-
tion.75,82 Similarly, a history of actinic keratoses or leukemias
and lymphomas also increase risk of cutaneous malignancy
incidence following transplantation. UV radiation—particularly
intense, intermittent exposure—has long been correlated with
cutaneous malignancy risk and this risk is further elevated in
transplant patients. Patients with light-colored eyes, hair, or
skin such as those with Fitzpatrick types I to III are at higher
risk because they are less shielded from the mutagenic e ects
of UV light.59 As discussed above, infection with tumorigenic
viruses increases the risk of cutaneous malignancy formation in
transplant patients who are immunosuppressed.43 These virus
associated cancers include KS (HIV) and SCC (HPV). Finally,
inherited cancer syndromes such as Gorlin’s syndrome and XP
increase incidence of cutaneous malignancies on their own and
among transplant recipients.
12.6.5 Immunosuppressive Medications
To prevent rejection following solid organ transplantation,
patients typically receive intense induction immunosuppres-
sion followed by a prolonged course of maintenance medica-
tions. Induction agents aim to deplete or impair T cell
responses, which are critical to coordinating rejection. Biologic
agents such as antithymocyte globulin (ATG), antilymphocyte
globulin (ADG), muromonab (OKT3), or alemtuzumab (Cam-
path) are used to deplete T cells. Other biologics include the
anti-CD25 monoclonal antibodies basiliximab and daclizumab,
which prevent interleukin-2 (IL-2) mediated T cell activation.
Specific induction regimens vary between transplant centers,
but they share the goal of preventing acute rejection and pre-
paring the immune system for maintenance therapy. Some of
these agents including ATG, OKT3, and anti-CD25 antibodies
have been shown to increase the risk of cutaneous malignancy
in heart transplant recipient.86
Traditional maintenance immunosuppression for most solid
organ transplants requires three drugs: a calcineurin inhibitor
(cyclosporine or tacrolimus), an antiproliferative agent (aza-
thioprine, mycophenolate, sirolimus, or everolimus), and corti-
costeroids. These medications are typically taken for life. Acute
rejection episodes require increases in immunosuppressive
doses or the use of additional agents. If by contrast the graft is
well tolerated, then maintenance dosing may be reduced or
individual drugs may be eliminated. Many transplant centers
are attempting minimal immunosuppressive strategies aimed
at avoiding the deleterious consequences of long-term, high-
dose immunosuppression. With respect to cutaneous malig-
nancies, patients on traditional three drug regimens had an
increased risk of cancer compared to patients treated with two
drugs only.71 Kidney transplant patients on triple therapy were
2.8 times more likely to acquire SCC than age-adjusted counter-
parts on azathioprine and prednisolone only.71 This risk is fur-
ther reduced when patients are treated on monotherapy with
calcineurin inhibitors. In a retrospective study of kidney trans-
plant patients over 40 years of age maintained on calcineurin
High-Risk Cutaneous Malignancies
240

inhibitors alone compared to those on dual or triple therapies,
the former patients had a significantly decreased risk of devel-
oping SCC.87 A trend toward decreased SCC risk was noted
among patients of all ages, but this was not statistically signifi-
cant. Patients on monotherapy had improved graft survival as
well. Strikingly, the ratio of SCC to BCC was 1:2 in the mono-
therapy arm at the end of the 12-year observation period,
approaching the 1:4 ratio observed in the general population.
This is in contrast to patients on dual or triple therapy who
showed the preponderance of SCC characteristic of transplant
patients. Taken together, these data suggest that monotherapy
with a calcineurin inhibitor ought to be preferred over dual and
triple drug maintenance regimens in patients with a high risk
of cutaneous malignancy. Nonetheless, even calcineurin inhibi-
tion alone carries a significant risk of cutaneous malignancy,
particularly when accomplished by the drug cyclosporine.
Cyclosporine has direct tumor-promoting properties in addi-
tion to inhibiting tumor surveillance. Thus, e ective but safer
maintenance strategies are still required.
One such approach is the use of immunosuppressive strat-
egies incorporating inhibitors of the mammalian target of rapa-
mycin (mTOR). These drugs—sirolimus and everolimus—
accomplish immunosuppression by preventing the proliferation
of T cells following antigenic challenge. Unlike cyclosporine,
they are non-nephrotoxic, making them particularly valuable
alternatives in the setting of kidney transplantation. Use of siro-
limus is associated with a decreased risk of developing cutane-
ous malignancies when compared with cyclosporine. In kidney
transplant recipients, the relative risk of developing both SCC
and BCC was reduced in patients on sirolimus immunosuppres-
sion and the mean time to skin cancer appearance was
increased.88 Furthermore, conversion from calcineurin inhibi-
tors to sirolimus in patients with known skin cancer may
improve outcomes.89,90 In one study of 53 kidney transplant
patients with nonmelanoma skin cancer, 37 exhibited tumor
regression.90 Intriguingly, mTOR inhibitors have been shown to
have direct antineoplastic e ects in other cancer types. Numer-
ous ongoing clinical trials aim to examine the e cacy of siroli-
mus and related inhibitors as cancer therapeutics. Early data
from these trials have been encouraging for patients with meta-
static renal cell carcinoma, neuroendocrine tumors of the pan-
creas, and certain kinds of breast cancers.91 Prospective clinical
trials to address the e cacy of sirolimus in treating cutaneous
malignancies in transplant patients are ongoing.
Other minimal immunosuppressive or immunomodulatory
strategies, such as the use of the CTLA4-Ig molecule belatacept
as a single maintenance agent, have been attempted. These
approaches are particularly valuable in life-enhancing trans-
plants such as vascularized composite allotransplantation of
hands or faces.92 However, the benefit of these regimens in
reducing cutaneous malignancy incidence remains to be
demonstrated.
12.6.6 Patient Education and
Prevention
The approach to cutaneous malignancies in transplant patients
begins with prevention. Given the high propensity of these
patients to develop skin cancer, every attempt must be made to
address modifiable risk factors and to identify lesions early.
Unfortunately, many transplant recipients do not remember being
counseled on their increased risk for skin cancer.93,94 These
patients benefit from evaluation at dedicated transplant dermatol-
ogy clinics before and after transplantation. Patients who are fol-
lowed at such clinics have higher compliance with preventative
measures and are more aware of the risks of cutaneous malig-
nancy.95,96 Pretransplantation visits should emphasize avoidance
of intense sun exposure or tanning bed use, as well as use of sun-
protective clothing and sunscreen. Existing skin lesions should be
catalogued for future follow-up and suspicious lesions should be
biopsied as warranted. This is particularly true in patients who
show evidence of extensive cumulative exposure to UV light.
These patients will have large areas of keratotic skin lesions
including actinic keratoses, papillomas, and porokeratoses. Much
of the skin in these areas will show evidence of epidermal dyspla-
sia, which can be a precursor of epithelial malignancy. Thus, a
large area of the skin in these patients is susceptible to malignant
transformation—a concept termed “field cancerization.” Keratotic
skin lesions in these patients should be aggressively treated using
cryosurgery, electrodessication and curettage, or topical 5-fluoro-
uracil (5-FU).97 Suspicious lesions should be biopsied early given
that it can be di cult to distinguish premalignant lesions from
SCC in areas of extensive damage.98,99
Transplant patients should be evaluated regularly in trans-
plant dermatology clinics—at least yearly if there is no evidence
of preexisting disease and as frequently as every 3 months in
patients with aggressive SCC or melanoma.93 There is evidence
that exposure to preventative measures decreases the incidence
of cutaneous malignancy. A prospective, case-control study of
heart, kidney, or lung transplant patients compared patients
who were given sun-protection education alone versus those
given education and unlimited free sunscreen with instructions
on application. Over the 2-year follow-up period, the latter
group demonstrated statistically significantly fewer invasive
SCCs and a nonsignificant trend toward decreased BCCs.100
12.6.7 Management of Cutaneous
Malignancies in Transplant Patients
Once cutaneous malignancies appear, management is guided by
their type and aggressiveness. Below we consider the role of
destructive and extirpative modalities, sentinel lymph node
biopsy (SLNB), radiation therapy, photodynamic therapy, and
preventative and curative chemotherapy for various types of
cutaneous malignancies.
12.6.8 Squamous Cell Carcinoma
A major meta-analysis by the Guidelines Committee of the
International Transplant-Skin Cancer Collaborative divided SCC
in transplant patients into less aggressive and more aggressive
lesions, and established corresponding management strategies.
Less aggressive lesions are defined as in Table 12.1.97 Lesions
with less aggressive characteristics on biopsy should be treated
by destructive or excisional modalities. Destructive techniques
include electrodessication and curettage or cryosurgery. These
methods can be used alone or in combination and are particu-
larly valuable in patients with multiple lesions. Excisional
High-Risk Cutaneous Malignancies
241

techniques include Mohs micrographic surgery and conven-
tional resection with pathologic assessment of margins. Mohs
surgery is the first choice for areas of high cosmetic sensitivity
such as the face. It allows for high cure rates while minimizing
resection of adjacent normal tissue.97 Conventional surgical
excision can be used in less critical anatomic regions or if the
patient is not a candidate for Mohs surgery. In organ transplant
patients, minimal margins are 4 to 6 mm.101
Aggressive SCCs are defined in Table 12.2. These are more
common in transplant patients than in the general population.
These lesions are best managed by a multidisciplinary team
including surgical oncologists and plastic and reconstructive
surgeons. At the time of presentation, a metastatic workup
should first be performed for patients with aggressive SCCs.
Ultimately, surgical excision by Mohs surgery or conventional
methods is the mainstay of management. Numerous studies
have documented the high cure rates achieved by Mohs sur-
gery.102,103,104 When Mohs surgery is not available or feasible,
excision with intraoperative frozen section margin control is
recommended. Excision with postoperative margin assessment
only is not ideal, but when it is required, margins of 4 to 6 mm
beyond surrounding erythema or subcutaneous invasion are
required. The lymph node status of patients with aggressive
SCCs should also be evaluated. Imaging with computed tomog-
raphy (CT) or magnetic resonance imaging (MRI) can be useful
in patients with high-thickness SCCs (>6 mm) in high-risk
areas.93,105 Comprehensive regional lymph node dissection is
recommended for patients with clinically palpable nodes. The
role of sentinel node biopsy in patients with aggressive SCCs
remains to be defined. One case series demonstrated a benefit
to sentinel node biopsy in detecting early nodal metastases
with a sensitivity of 88% and negative predictive value of
0.94.106 These procedures can be performed with minimal
morbidity by experienced practitioners and are therefore rec-
ommended in most cases. Further prospective studies are
required, however, to determine which patients with aggressive
SCCs would most benefit from sentinel node evaluation.
Numerous adjunctive modalities exist for patients with SCC.
For patients with multiple lesions in areas of field cancerization,
preventative therapies can be added following surgical excision.
These include topical 5-FU, imiquimod, and photodynamic
therapy.93 Topical 5-FU can cause regression or elimination of
premalignant lesions in some cases. Imiquimod is an immune
modulator that has been approved for the treatment of SCCs
Table 12.1 Characteristics of less aggressive squamous cell carcinoma
in transplant patients
Characteristic
Size

<0.6 cm on mask areas of face, genitalia, hands,
feet
<1 cm cheeks, forehead, neck, scalp
<2 cm trunk and extremities
Growth rate

Static or slowly growing
Ulceration

No
Border

Distinct and well defined
Satellite lesions

No
Histology

In situ, keratoacanthoma type, well differentiated,
invasion limited to papillary dermis, no neuro-
tropism, no perivascular/intravascular invasion
Source: Adapted from Stasko T, Brown MD, Carucci JA, et al. Guidelines
for the management of squamous cell carcinoma in organ transplant
recipients. Dermatol Surg 2004;30(4, Pt 2):642–650.
Table 12.2 Characteristics of more aggressive squamous cell carcinoma (SCC) in transplant patients # M
Characteristic
Number of lesions

Multiple SCCs
Size

>0.6 cm on mask areas of face, genitalia, hands, feet
>1 cm cheeks, forehead, neck, scalp
>2 cm trunk and extremities
Growth

Rapid
Ulceration

Yes
Border

Indistinct clinical borders
Satellite lesions

Yes
Location

Central face, eyelids, eyebrows, periorbital, nose, lips, chin, mandible, preauricular or postauricular area, temple, ear,
genitalia, digits
Occurrence in damaged skin Occurrence in scar, area of chronic inflammation, or previous radiation
Recurrence

Tumor returns after previous treatment
Histology

Extension into subcutaneous fat, perineural invasion/inflammation, perivascular/intravascular infiltration, poorly differ-
entiated
Source: Adapted from Stasko T, Brown MD, Carucci JA, et al. Guidelines for the management of squamous cell carcinoma in organ transplant recipients.
Dermatol Surg 2004;30(4, Pt 2):642–650.
High-Risk Cutaneous Malignancies
242

and BCCs. Several studies have documented its safety and e -
cacy in transplant patients. In treatment of actinic keratoses, for
example, one multisite study found clearance rates of 62% for
patients treated on imiquimod compared to 0% for controls.107
Another study found a decrease in the incidence of SCCs in kid-
ney transplant patients treated with imiquimod.108
Photodynamic therapy (PDT) is another adjunctive modality
in the management of SCC. It entails topical application of a
photosensitive chemical in a ected areas of skin followed by
light administration. Activation of the photosensitizer by light
leads to formation of reactive oxygen species that destroy
tumor cells. Perrett and colleagues compared PDTusing the top-
ical photosensitizer methyl aminolevulinate (MAL) to treatment
with 5-FU in a small group of organ transplant recipients with
epidermal dysplasia.109 Nearly 90% of the lesions treated with
PDT were cleared compared to only 11% treated with 5-FU. In
addition, PDT was subjectively preferred by patients, and both
patients and clinicians noted improved cosmetic outcome with
PDT. This modality has also proven e ective in the manage-
ment of actinic keratoses in transplant recipients.110 While PDT
is e ective in the management of premalignant lesions,
whether it ultimately prevents the formation of SCC is less clear.
One randomized controlled trial failed to demonstrate a benefit
of PDT in SCC prevention at 2-year follow-up, while another
smaller trial appeared to show a significant reduction in SCC
incidence with PDT.111,112 Firm conclusions on the role of PDT
in preventing SCC in transplant patients will require larger
studies. Nonetheless, the modality has a role in treating prema-
lignant skin in these patients who are at high risk of developing
cutaneous malignancy. In summary, for patients with less
aggressive SCCs, 5-FU, imiquimod, and PDT can supplement
surgical resection and treat premalignant epidermal dysplasia
in areas of field cancerization.
Transplant patients with aggressive SCCs may benefit from
other adjunctive modalities. Systemic retinoid administration
can be used as a preventative measure for SCC in these patients.
Due to the significant toxicities associated with this therapy, it
should be reserved for patients with an extremely high propen-
sity for SCC formation—5 to 10 lesions per year—or in those
with particularly aggressive SCCs.93 Retinoids such as acretin or
isotretinoin are extremely teratogenic and are therefore abso-
lutely contraindicated in women who are pregnant or may
become pregnant. Acretin can lead to hyperlipidemia and liver
dysfunction. These side e ects must be carefully monitored and
doses adjusted accordingly. Multiple studies have borne out the
e ectiveness of retinoids in preventing SCC in transplant recipi-
ents.113,114,115,116,117 However, these medications must be con-
tinued indefinitely because treatment interruption can lead to
more rapid and aggressive SCC formation.
Capecitabine—a prodrug of 5-FU—has also been used to good
e ect in patients with aggressive SCCs. In one small study of
four patients with aggressive disease, complete regression was
achieved in two patients.118 Another case series of just three
patients showed a decreased incidence of new SCCs over a 6-
month period.119 As with systemic retinoids, toxicities limit the
use of capecitabine to patients with the most aggressive SCCs.
Nephrotoxicity, neutropenia, and gastrointestinal toxicities
require dose modification or elimination.
Radiotherapy can also be indicated in patients with aggres-
sive SCCs or in patients in whom complete surgical resection
cannot be achieved. Aggressive SCCs such as recurrent lesions,
tumors with depth of invasion more than 2 mm, tumors more
than 2 cm in diameter, tumors that exhibit perineural or lym-
phatic/vascular invasion, or poorly di erentiated tumors all
carry poorer prognosis and may benefit from radiotherapy. A
review of 167 patients treated over 20 years with surgery and
radiation or surgery alone demonstrated a clear benefit to mul-
timodal therapy with such patients having lower recurrence
and improved long-term survival.120 As this study was carried
out in immunocompetent patients, it remains to be seen
whether similar improvements in outcome can be achieved in
patients with SCCs following organ transplantation.
In transplant patients with SCC, alterations in immunosup-
pressive regimens may be warranted. Immunosuppression
should always be reduced to the lowest level compatible with
graft survival. Several studies have demonstrated the superior-
ity of single or dual medication regimens over traditional triple
immunosuppressive therapy in reducing risk of cutaneous
malignancies.71,87 In addition to reducing the number of agents,
replacement of calcineurin inhibitors with mTOR inhibitors
may further improve outcomes. Several studies have demon-
strated decreased malignancy risk and improved outcomes in
patients treated with the mTOR inhibitor sirolimus.89,91 In one
randomized, multicenter trial, patients with SCC who switched
from calcineurin to sirolimus had longer cancer-free survival
and an overall decreased incidence of new SCC development.121
In addition, an ongoing clinical trial is testing whether sirolimus
is e ective in directly treating SCC among kidney transplant
recipients.122 For both decreasing the risk of new SCCs and
potential treatment of existing SCCs, use of mTOR inhibitors in
place of calcineurin inhibitors is recommended whenever
feasible.
Transplant recipients who develop metastatic SCC fare more
poorly than their immunocompetent counterparts.66 Three-
year disease-free survival is approximately 50%. Patients who
are immunocompromised from transplantation or other malig-
nancies have a higher rate of locoregional relapse following SCC
treatment.123 Adjunctive radiation therapy is of limited e ec-
tiveness in patients with metastatic SCC. Unlike patients with
BCC, those with advanced SCC have a median time to recur-
rence of only 5 months in one study, and the majority of these
patients succumb to their disease.124 Traditional chemothera-
peutic agents such as platinum-based compounds are also of
limited e cacy.
Novel targeted therapeutics do show some promise in
advanced SCC, however. One set of agents target epidermal
growth factor receptor (EGFR) family members. These include
the monoclonal antibodies cetuximab and panitumumab, and
small molecules gefitinib and erlotinib. Cetuximab has been
approved for the treatment of advanced SCC of the head and
neck as a single agent and in combination with radiation and
chemotherapy. Its role in the management of cutaneous SCC is
being explored. A prospective phase II study of cetuximab in
patients with unresecatable cutaneous SCC demonstrated an
encouraging disease control rate at 6 weeks of nearly 70%.125 It
will be interesting to see if these results are confirmed in longer
and larger phase III investigations. A phase II study of gefitinib
revealed a complete response rate of 18% with acceptable toler-
ability, suggesting that this may be a useful agent alone or in
combination with resection and/or radiotherapy.126 Further
High-Risk Cutaneous Malignancies
243

studies to identify biomarkers predictive of response to gefiti-
nib are also warranted.122 Other molecular targets for advanced
SCC such as the NOTCH and PI3K-AKT pathways are also being
explored and may provide more therapeutic options in the
future.122
12.6.9 Basal Cell Carcinoma
While BCC occurs much more frequently in transplant recip-
ients compared to im m unocompetent counterparts, it does
not behave in a m uch m ore aggressive fashion. This is in
contrast to SCC, w hich is m ore aggressive in transplant
patients. Transplant patients with BCC are not m ore likely to
succum b to their disease, nor do they su er a higher inci-
dence of metastasis.127 Therefore, the m anagement of BCC in
these patients parallels the management in patients who are
not imm unosuppressed. A primary focus is on prevention,
w ith counseling on sun avoidance and frequent surveillance
being param ount. When locally contained BCCs do arise,
destructive m odalities such as electrodessication and curet-
tage or cryoablation may su ce. Topical 5-FU can also be
used for sm aller lesions. Mohs micrographic surgery and
conventional surgical resection o er an excellent chance of
cure as well.
In patients who develop advanced disease, surgery w ith
or w ithout radiation is the traditional treatm ent of choice.
Recently, targeted therapeutics that inhibit the Hh pathway
have o ered a m edical alternative in patients with advanced
BCC. These agents were developed following the discovery
that m utations in the Hh pathway underlie fam ilial BCC and
m any spontaneous cases.128,129,130,131,132 Transplant recipi-
ents were excluded from the original trials establishing the
e cacy of these agents, however. Recently, a case report
docum ented the use of the Hh pathway inhibitor vismode-
gib in a heart transplant recipient with a history of multiply
recurrent BCC.133 After 24 weeks of therapy, he demon-
strated stabilization of his disease and histologic evidence of
tum or response to the agent. Further studies on the use of
targeted therapies for BCC in transplant recipients are
warranted.
12.6.10 Melanoma
Melanom a is among the most aggressive of cutaneous m alig-
nancies, and the clear role of the im mune system in control-
ling m elanom a m akes the prospects of imm unosuppression
particularly fraught. The Melanom a Working Group of the
International Transplant Skin Cancer Collaborative identifies
three scenarios of particular concern: (1) patients w ith a
history of m elanom a who are contemplating organ trans-
plantation, (2) potential donors with a history of melanom a,
and (3) transplant recipients w ho develop m elanom a de
novo.134 For patients w ith a history of m elanoma, the deci-
sion to proceed w ith transplantation is in part based on
Breslow thickness. Based on risk of recurrence, the Working
Group suggest proceeding without delay in patients with
m elanoma in situ, waiting at least 2 years in patients with
m elanoma less than 2 m m and negative sentinel node
biopsy, and waiting 5 years in patients w ith m ore than
2 m m lesions. Patients w ith nodal involvem ent or m etastatic
disease should not be transplanted. Of course, these recom -
m endations m ust be tempered by the severity of the disease
processes necessitating transplantation. Each situation
should ideally be evaluated by a multidisciplinary team of
transplant surgeons, im munologists, and derm atologists.
While rare, case reports of melanoma transmission from
transplant donor to recipient have been published.93 In one
study, melanoma figured in 12 of 167 malignancies that were
transferred from donor to recipient.135 Clearly prevention
should be paramount, with a whole-body skin examination
performed prior to organ donation. When melanoma is passed
from donor to recipient, consensus opinion favors removal of
the transplanted organ and any resectable metastases coupled
with discontinuation of immunosuppression.134
Once diagnosed, the mainstay of melanoma management in
transplant recipients is surgical excision with margin control
just as it is in immunocompetent individuals. Resection mar-
gins should follow guidelines based on Breslow thickness. Given
the importance of lymph node status on prognosis and man-
agement in melanoma, patients with intermediate and thick
melanomas should undergo SLNB at the time of tumor resec-
tion. Sentinel node sampling may even be considered in thinner
melanomas given the more aggressive course of melanoma in
transplant patients and the relatively low morbidity of SLNB.
Lymph node dissection should be performed when feasible in
patients with Stage III disease.134
Medical management of melanoma in transplant recipients
begins with minimization of immunosuppression. Novel immu-
nostimulatory molecules based on immune-checkpoint blo-
ckade should also be considered. As discussed earlier, these
agents have shown encouraging results in patients with
advanced disease. The first reports of immunostimulatory
agents in treating melanoma among transplant recipients have
been encouraging. Partial responses were achieved in two kid-
ney transplant patients with metastatic melanoma who were
treated with ipilimumab.136 Interestingly, these patients did not
develop episodes of acute rejection, which may reflect the long-
standing nature of their transplants and possible tolerance to
the grafts. These agents are beginning to be used in combina-
tion with molecularly targeted therapeutics such as BRAF inhib-
itors which aim to inhibit proteins critical to tumor
progression.137 If the toxicities associated with such combina-
tions can be overcome, patients with advanced melanoma may
achieve more durable responses to treatment.
12.7 Conclusion
Cutaneous malignancies are becoming more prevalent in devel-
oped countries. High-risk cutaneous malignancies resulting
from inherited predisposition or immunosuppression are par-
ticularly devastating given their aggressive courses and propen-
sity for recurrence. Prevention should be the foremost concern
for providers who treat these patients. Sun avoidance and skin
surveillance at dedicated dermatology clinics are critical. When
cutaneous malignancies occur, prompt surgical and medical
management, with alterations in immunosuppression when
possible, is advised. The development of molecularly targeted
therapies and immunomodulatory agents o ers new hope to
patients with these challenging conditions.
High-Risk Cutaneous Malignancies
244

References
[1] Nikolaou V, Stratigos AJ, Tsao H. Hereditary nonmelanoma skin cancer.
Semin Cutan Med Surg. 2012; 31(4):204–210
[2] DiGiovanna JJ, Kraemer KH. Shining a light on xeroderma pigmentosum. J
Invest Dermatol. 2012; 132(3, Pt 2):785–796
[3] Kraemer KH, Lee MM, Andrews AD, Lambert WC. The role of sunlight and
DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma
pigmentosum paradigm. Arch Dermatol. 1994; 130(8):1018–1021
[4] Oh KS, Emmert S, Tamura D, DiGiovanna JJ, Kraemer KH. Multiple skin can-
cers in adults with mutations in the XP-E (DDB2) DNA repair gene. J Invest
Dermatol. 2011; 131(3):785–788
[5] Athar M, Li C, Kim AL, Spiegelman VS, Bickers DR. Sonic hedgehog signaling
in Basal cell nevus syndrome. Cancer Res. 2014; 74(18):4967–4975
[6] Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer.
2008; 8(10):743–754
[7] Kimonis VE, Mehta SG, Digiovanna JJ, Bale SJ, Pastakia B. Radiological fea-
tures in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syn-
drome. Genet Med. 2004; 6(6):495–502
[8] Basset-Seguin N, Sharpe HJ, de Sauvage FJ. E cacy of Hedgehog pathway
inhibitors in Basal cell carcinoma. Mol Cancer Ther. 2015; 14(3):633–641
[9] Czajkowski R, Placek W, Drewa G, Czajkowska A, Uchańska G. FAMMM syn-
drome: pathogenesis and management. Dermatol Surg. 2004; 30(2, Pt
2):291–296
[10] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated
population burden of selected autoimmune diseases in the United States.
Clin Immunol Immunopathol. 1997; 84(3):223–243
[11] Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in
people with HIV/AIDS compared with immunosuppressed transplant recipi-
ents: a meta-analysis. Lancet. 2007; 370(9581):59–67
[12] Burnet M. Cancer: a biological approach. III. Viruses associated with neoplas-
tic conditions. IV. Practical applications. BMJ. 1957; 1(5023):841–847
[13] Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res.
1970; 13:1–27
[14] Kinlen LJ, Webster AD, Bird AG, et al. Prospective study of cancer in patients
with hypogammaglobulinaemia. Lancet. 1985; 1(8423):263–266
[15] Mueller BU, Pizzo PA. Cancer in children with primary or secondary immu-
nodeficiencies. J Pediatr. 1995; 126(1):1–10
[16] Hayward AR, Levy J, Facchetti F, et al. Cholangiopathy and tum ors of the pan-
creas, liver, and biliary tree in boys with X-linked immunodeficiency with
hyper-IgM. J Immunol. 1997; 158(2):977–983
[17] Engels EA, Pfei er RM, Fraumeni JF, Jr, et al. Spectrum of cancer risk among
US solid organ transplant recipients. JAMA. 2011; 306(17):1891–1901
[18] Dantal J, Hourm ant M, Cantarovich D, et al. E ect of long-term im mu-
nosuppression in kidney-graft recipients on cancer incidence: rando-
mised comparison of two cyclosporin regim ens. Lancet. 1998; 351
(9103):623–628
[19] Hojo M, Morim oto T, Maluccio M, et al. Cyclosporine induces cancer progres-
sion by a cell-autonomous mechanism. Nature. 1999; 397(6719):530–534
[20] Wu X, Nguyen BC, Dziunycz P, et al. Opposing roles for calcineurin and ATF3
in squamous skin cancer. Nature. 2010; 465(7296):368–372
[21] Bottomley WW, Ford G, Cunli e WJ, Cotterill JA. Aggressive squamous cell
carcinomas developing in patients receiving long-term azathioprine. Br J
Dermatol. 1995; 133(3):460–462
[22] O’Donovan P, Perrett CM, Zhang X, et al. Azathioprine and UVA light gener-
ate mutagenic oxidative DNA damage. Science. 2005; 309(5742):1871–1874
[23] Cli ord GM, Polesel J, Rickenbach M, et al. Swiss HIV Cohort. Cancer risk
in the Swiss HIV Cohort Study: associations with im munodeficiency,
sm oking, and highly active antiretroviral therapy. J Natl Cancer Inst.
2005; 97(6):425–432
[24] Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of
non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr.
2009; 52(5):611–622
[25] Sigel K, Wisnivesky J, Gordon K, et al. HIV as an independent risk factor for
incident lung cancer. AIDS. 2012; 26(8):1017–1025
[26] Corthay A. Does the immune system naturally protect against cancer? Front
Immunol. 2014; 5:197
[27] Guiguet M, Boué F, Cadranel J, Lang JM, Rosenthal E, Costagliola D, Clinical
Epidemiology Group of the FHDH-ANRS CO4 cohort. E ect of immunodefi-
ciency, HIV viral load, and antiretroviral therapy on the risk of individual
malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol.
2009; 10(12):1152–1159
[28] Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prog-
nostic e ect of epithelial and stromal lymphocyte infiltration in non-small
cell lung cancer. Clin Cancer Res. 2008; 14(16):5220–5227
[29] Kawai O, Ishii G, Kubota K, et al. Predominant infiltration of macrophages
and CD8(+) T Cells in cancer nests is a significant predictor of survival in
stage IV nonsmall cell lung cancer. Cancer. 2008; 113(6):1387–1395
[30] Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8 +lympho-
cytes predict clinical outcome in breast cancer. J Clin Oncol. 2011; 29
(15):1949–1955
[31] Kluger HM, Zito CR, Barr ML, et al. Characterization of PD-L1 Expression and
Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable
Anatomic Sites. Clin Cancer Res. 2015; 21(13):3052–3060
[32] Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab
in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711–723
[33] Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for
previously untreated metastatic melanoma. N Engl J Med. 2011; 364
(26):2517–2526
[34] Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatm ent-naive
patients with advanced melanoma who received ipilimumab plus dacarba-
zine in a phase III trial. J Clin Oncol. 2015; 33(10):1191–1196
[35] Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated mela-
noma without BRAF mutation. N Engl J Med. 2015; 372(4):320–330
[36] Rangwala S, Tsai KY. Roles of the immune system in skin cancer. Br J Derma-
tol. 2011; 165(5):953–965
[37] Kütting B, Drexler H. UV-induced skin cancer at workplace and evidence-
based prevention. Int Arch Occup Environ Health. 2010; 83(8):843–854
[38] Kripke ML. Antigenicity of murine skin tumors induced by ultraviolet light. J
Natl Cancer Inst. 1974; 53(5):1333–1336
[39] Kripke ML. Latency, histology, and antigenicity of tum ors induced by
ultraviolet light in three inbred m ouse strains. Cancer Res. 1977; 37
(5):1395–1400
[40] Yoshikawa T, Rae V, Bruins-Slot W, Van den Berg JW, Taylor JR, Streilein JW.
Susceptibility to e ects of UVB radiation on induction of contact hypersensi-
tivity as a risk factor for skin cancer in humans. J Invest Dermatol. 1990; 95
(5):530–536
[41] Cooper KD, Oberhelman L, Hamilton TA, et al. UVexposure reduces immuni-
zation rates and promotes tolerance to epicutaneous antigens in humans:
relationship to dose, CD1a-DR+epidermal macrophage induction, and Lan-
gerhans cell depletion. Proc Natl Acad Sci U S A. 1992; 89(18):8497–8501
[42] Damian DL, Halliday GM, Barnetson RS. Broad-spectrum sunscreens provide
greater protection against ultraviolet-radiation-induced suppression of con-
tact hypersensitivity to a recall antigen in humans. J Invest Dermatol. 1997;
109(2):146–151
[43] Nindl I, Rösl F. Molecular concepts of virus infections causing skin cancer in
organ transplant recipients. Am J Transplant. 2008; 8(11):2199–2204
[44] Dubina M, Goldenberg G. Viral-associated nonmelanoma skin cancers: a
review. Am J Dermatopathol. 2009; 31(6):561–573
[45] Boukamp P. Non-melanoma skin cancer: what drives tum or development
and progression? Carcinogenesis. 2005; 26(10):1657–1667
[46] Kassem A, Schöpflin A, Diaz C, et al. Frequent detection of Merkel cell polyo-
mavirus in human Merkel cell carcinomas and identification of a unique
deletion in the VP1 gene. Cancer Res. 2008; 68(13):5009–5013
[47] Penn I, First MR. Merkel’s cell carcinoma in organ recipients: report of 41
cases. Transplantation. 1999; 68(11):1717–1721
[48] Antm an K, Chang Y. Kaposi’s sarcom a. N Engl J Med. 2000; 342
(14):1027–1038
[49] Moore PS, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi’s
sarcoma in patients with and without HIV infection. N Engl J Med. 1995;
332(18):1181–1185
[50] Dictor M, Rambech E, Way D, Witte M, Bendsöe N. Human herpesvirus 8
(Kaposi’s sarcoma-associated herpesvirus) DNA in Kaposi’s sarcoma lesions,
AIDS Kaposi’s sarcoma cell lines, endothelial Kaposi’s sarcoma simulators,
and the skin of immunosuppressed patients. Am J Pathol. 1996; 148
(6):2009–2016
[51] Ensoli B, Sgadari C, Barillari G, Sirianni MC, Stürzl M, Monini P. Biology of
Kaposi’s sarcoma. Eur J Cancer. 2001; 37(10):1251–1269
[52] Grabar S, Abraham B, Mahamat A, Del Giudice P, Rosenthal E, Costagliola D.
Di erential impact of combination antiretroviral therapy in preventing
Kaposi’s sarcoma with and without visceral involvement. J Clin Oncol. 2006;
24(21):3408–3414
[53] Cheung MC, Pantanowitz L, Dezube BJ. AIDS-related malignancies: emerging
challenges in the era of highly active antiretroviral therapy. Oncologist.
2005; 10(6):412–426
High-Risk Cutaneous Malignancies
245

[54] Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, Di Trolio R, De Placido
S, Dezube BJ. Management of AIDS-related Kaposi’s sarcoma. Lancet Oncol.
2007; 8(2):167–176
[55] Burgi A, Brodine S, Wegner S, et al. Incidence and risk factors for the occur-
rence of non-AIDS-defining cancers among human immunodeficiency
virus-infected individuals. Cancer. 2005; 104(7):1505–1511
[56] Franceschi S, Dal Maso L, Arniani S, et al. Risk of cancer other than Kaposi’s
sarcoma and non-Hodgkin’s lymphoma in persons with AIDS in Italy. Cancer
and AIDS Registry Linkage Study. Br J Cancer. 1998; 78(7):966–970
[57] Goedert JJ, Coté TR, Virgo P, et al. Spectrum of AIDS-associated malignant
disorders. Lancet. 1998; 351(9119):1833–1839
[58] Wilkins K, Turner R, Dolev JC, LeBoit PE, Berger TG, Maurer TA. Cutaneous
malignancy and human immunodeficiency virus disease. J Am Acad Derma-
tol. 2006; 54(2):189–206, quiz 207–210
[59] Rodrigues LK, Klencke BJ, Vin-Christian K, et al. Altered clinical course of
malignant melanoma in HIV-positive patients. Arch Dermatol. 2002; 138
(6):765–770
[60] Zwald FO, Brown M. Skin cancer in solid organ transplant recipients:
advances in therapy and managem ent: part I. Epidem iology of skin can-
cer in solid organ transplant recipients. J Am Acad Derm atol. 2011; 65
(2):253–261, quiz 262
[61] Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N
Engl J Med. 2003; 348(17):1681–1691
[62] Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology,
pathogenesis, and management. J Am Acad Dermatol. 2002; 47(1):1–17,
quiz 18–20
[63] Parada MT, Sepúlveda C, Alba A, Salas A. Malignancy development in lung
transplant patients. Transplant Proc. 2011; 43(6):2316–2317
[64] Otley CC, Pittelkow MR. Skin cancer in liver transplant recipients. Liver
Transpl. 2000; 6(3):253–262
[65] Penn I. Neoplastic complications of transplantation. Semin Respir Infect.
1993; 8(3):233–239
[66] Martinez JC, Otley CC, Stasko T, et al. Transplant-Skin Cancer Collaborative.
Defining the clinical course of metastatic skin cancer in organ transplant
recipients: a multicenter collaborative study. Arch Dermatol. 2003; 139
(3):301–306
[67] Tufaro AP, Chuang JC, Prasad N, Chuang A, Chuang TC, Fischer AC. Molecular
markers in cutaneous squamous cell carcinoma. Int J Surg Oncol. 2011;
2011:231475
[68] Prasad NB, Fischer AC, Chuang AY, et al. Di erential expression of degra-
dome components in cutaneous squamous cell carcinomas. Mod Pathol.
2014; 27(7):945–957
[69] Kasiske BL, Vazquez MA, Harmon WE, et al. American Society of Transplan-
tation. Recommendations for the outpatient surveillance of renal transplant
recipients. J Am Soc Nephrol. 2000; 11 Suppl 15:S1–S86
[70] Zavos G, Karidis NP, Tsourouflis G, et al. Nonmelanoma skin cancer after
renal transplantation: a single-center experience in 1736 transplantations.
Int J Dermatol. 2011; 50(12):1496–1500
[71] Jensen P, Hansen S, Møller B, et al. Skin cancer in kidney and heart trans-
plant recipients and di erent long-term immunosuppressive therapy regi-
mens. J Am Acad Dermatol. 1999; 40(2, Pt 1):177–186
[72] Lindelöf B, Sigurgeirsson B, Gäbel H, Stern RS. Incidence of skin cancer in
5356 patients following organ transplantation. Br J Dermatol. 2000; 143
(3):513–519
[73] Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Inci-
dence of skin cancer after renal transplantation in The Netherlands. Trans-
plantation. 1990; 49(3):506–509
[74] Yu SH, Bordeaux JS, Baron ED. The immune system and skin cancer. Adv Exp
Med Biol. 2014; 810:182–191
[75] Bouwes Bavinck JN, Euvrard S, Naldi L, et al. EPI-HPV-UV-CA group. Ker-
atotic skin lesions and other risk factors are associated w ith skin cancer
in organ-transplant recipients: a case-control study in The Netherlands,
United Kingdom, Germ any, France, and Italy. J Invest Derm atol. 2007;
127(7):1647–1656
[76] Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Lengerich EJ.
Increased incidence of melanoma in renal transplantation recipients. Cancer.
2005; 104(9):1962–1967
[77] Kanitakis J, Baldassini S, Lora V, Euvrard S. BRAF mutations in melanocytic
tum ors (nevi and melanomas) from organ transplant recipients. Eur J Der-
matol. 2010; 20(2):167–171
[78] Woodle ES, Hanaway M, Buell J, et al. Israel Penn International Transplant
Tumor Registry. Kaposi sarcoma: an analysis of the US and international
experiences from the Israel Penn International Transplant Tumor Registry.
Transplant Proc. 2001; 33(7–8):3660–3661
[79] Allen UD. Human herpesvirus type 8 infections among solid organ trans-
plant recipients. Pediatr Transplant. 2002; 6(3):187–192
[80] Rockville Merkel Cell Carcinom a G, Rockville Merkel Cell Carcinom a
Group. Merkel cell carcinom a: recent progress and current priorities on
etiology, pathogenesis, and clinical management. J Clin Oncol. 2009; 27
(24):4021–4026
[81] Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus
in human Merkel cell carcinoma. Science. 2008; 319(5866):1096–1100
[82] Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN. Clinical risk factors
associated with nonmelanoma skin cancer in renal transplant recipients.
Am J Kidney Dis. 2000; 36(1):167–176
[83] Dyall-Smith D, Ross JB. Cutaneous malignancies in renal transplant recipi-
ents from Nova Scotia, Canada. Australas J Dermatol. 1995; 36(2):79–82
[84] Euvrard S, Kanitakis J, Cochat P, Claudy A. Skin cancers following pediatric
organ transplantation. Dermatol Surg. 2004; 30(4, Pt 2):616–621
[85] Penn I. De novo malignances in pediatric organ transplant recipients. Pediatr
Transplant. 1998; 2(1):56–63
[86] Geusau A, Dunkler D, Messeritsch E, et al. Non-melanoma skin cancer and
its risk factors in an Austrian population of heart transplant recipients
receiving induction therapy. Int J Dermatol. 2008; 47(9):918–925
[87] Abou Ayache R, Thierry A, Bridoux F, et al. Long-term maintenance of calci-
neurin inhibitor monotherapy reduces the risk for squamous cell carcinomas
after kidney transplantation compared with bi- or tritherapy. Transplant
Proc. 2007; 39(8):2592–2594
[88] Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclo-
sporine withdrawal reduces the risk for cancer in adult renal transplanta-
tion. J Am Soc Nephrol. 2006; 17(2):581–589
[89] Fernández A, Marcén R, Pascual J, et al. Conversion from calcineurin inhibi-
tors to everolimus in kidney transplant recipients with malignant neoplasia.
Transplant Proc. 2006; 38(8):2453–2455
[90] de Fijter JW. Use of proliferation signal inhibitors in non-melanoma skin
cancer following renal transplantation. Nephrol Dial Transplant. 2007; 22
Suppl 1:i23–i26
[91] Sun SY. mTOR kinase inhibitors as potential cancer therapeutic drugs. Can-
cer Lett. 2013; 340(1):1–8
[92] Schneeberger S, Khalifian S, Brandacher G. Immunosuppression and moni-
toring of rejection in hand transplantation. Tech Hand Up Extrem Surg.
2013; 17(4):208–214
[93] Zwald FO, Brown M. Skin cancer in solid organ transplant recipients:
advances in therapy and management: part II. Managem ent of skin can-
cer in solid organ transplant recipients. J Am Acad Derm atol. 2011; 65
(2):263–279, quiz 280
[94] Seukeran DC, Newstead CG, Cunli e WJ. The compliance of renal transplant
recipients with advice about sun protection measures. Br J Dermatol. 1998;
138(2):301–303
[95] Ismail F, Mitchell L, Casabonne D, et al. Specialist dermatology clinics for
organ transplant recipients significantly improve compliance with photo-
protection and levels of skin cancer awareness. Br J Dermatol. 2006; 155
(5):916–925
[96] Clowers-Webb HE, Christenson LJ, Phillips PK, et al. Educational out-
com es regarding skin cancer in organ transplant recipients: random ized
intervention of intensive vs standard education. Arch Derm atol. 2006;
142(6):712–718
[97] Stasko T, Brown MD, Carucci JA, et al. International Transplant-Skin Cancer
Collaborative, European Skin Care in Organ Transplant Patients Network.
Guidelines for the management of squamous cell carcinoma in organ trans-
plant recipients. Dermatol Surg. 2004; 30(4, Pt 2):642–650
[98] Blessing K, McLaren KM, Benton EC, et al. Histopathology of skin lesions in
renal allograft recipients–an assessment of viral features and dysplasia. His-
topathology. 1989; 14(2):129–139
[99] King GN, Healy CM, Glover MT, et al. Increased prevalence of dysplastic and
malignant lip lesions in renal-transplant recipients. N Engl J Med. 1995; 332
(16):1052–1057
[100] Ulrich C, Jürgensen JS, Degen A, et al. Prevention of non-melanoma skin can-
cer in organ transplant patients by regular use of a sunscreen: a 24 months,
prospective, case-control study. Br J Dermatol. 2009; 161 Suppl 3:78–84
[101] Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous
squamous cell carcinoma. J Am Acad Dermatol. 1992; 27(2, Pt 1):241–248
[102] Nguyen TH, Ho DQ. Nonmelanoma skin cancer. Curr Treat Options Oncol.
2002; 3(3):193–203
High-Risk Cutaneous Malignancies
246

[103] Rowe DE, Carroll RJ, Day CL, Jr. Prognostic factors for local recurrence, meta-
stasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip.
Implications for treatment modality selection. J Am Acad Dermatol. 1992;
26(6):976–990
[104] Sinclair RD, Dawber RP. Cryosurgery of malignant and premalignant diseases
of the skin: a simple approach. Australas J Dermatol. 1995; 36(3):133–142
[105] Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determin-
ing prognosis of cutaneous squamous-cell carcinoma: a prospective study.
Lancet Oncol. 2008; 9(8):713–720
[106] Wagner JD, Evdokimow DZ, Weisberger E, et al. Sentinel node biopsy for
high-risk nonmelanoma cutaneous malignancy. Arch Dermatol. 2004; 140
(1):75–79
[107] Ulrich C, Busch JO, Meyer T, et al. Successful treatment of multiple actinic
keratoses in organ transplant patients with topical 5% imiquimod: a report
of six cases. Br J Dermatol. 2006; 155(2):451–454
[108] Brown VL, Atkins CL, Ghali L, Cerio R, Harwood CA, Proby CM. Safety and
e cacy of 5% imiquimod cream for the treatment of skin dysplasia in high-
risk renal transplant recipients: randomized, double-blind, placebo-con-
trolled trial. Arch Dermatol. 2005; 141(8):985–993
[109] Perrett CM, McGregor JM, Warwick J, et al. Treatment of post-transplant pre-
malignant skin disease: a randomized intrapatient comparative study of 5-
fluorouracil cream and topical photodynamic therapy. Br J Dermatol. 2007;
156(2):320–328
[110] Piaserico S, Belloni Fortina A, Rigotti P, et al. Topical photodynamic therapy
of actinic keratosis in renal transplant recipients. Transplant Proc. 2007; 39
(6):1847–1850
[111] de Graaf YG, Kennedy C, Wolterbeek R, Collen AF, Willemze R, Bouwes
Bavinck JN. Photodynamic therapy does not prevent cutaneous squamous-
cell carcinoma in organ-transplant recipients: results of a randomized-con-
trolled trial. J Invest Dermatol. 2006; 126(3):569–574
[112] Willey A, Mehta S, Lee PK. Reduction in the incidence of squamous cell carci-
noma in solid organ transplant recipients treated with cyclic photodynamic
therapy. Dermatol Surg. 2010; 36(5):652–658
[113] Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer
and reduction of keratotic skin lesions during acitretin therapy in renal
transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol.
1995; 13(8):1933–1938
[114] Harwood CA, Leedham -Green M, Leigh IM, Proby CM. Low-dose reti-
noids in the prevention of cutaneous squam ous cell carcinom as in organ
transplant recipients: a 16-year retrospective study. Arch Derm atol.
2005; 141(4):456–464
[115] DiGiovanna JJ. Retinoid chemoprevention in the high-risk patient. J Am Acad
Dermatol. 1998; 39(2, Pt 3):S82–S85
[116] McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal trans-
plant recipients: 5 years of experience using low-dose acitretin. Br J Derma-
tol. 1999; 140(4):656–660
[117] George R, Weightman W, Russ GR, Bannister KM, Mathew TH. Acitretin for
chemoprevention of non-melanoma skin cancers in renal transplant recipi-
ents. Australas J Dermatol. 2002; 43(4):269–273
[118] Dooley M, Goa KL. Capecitabine. Drugs. 1999; 58(1):69–76, discussion
77–78
[119] Endrizzi BT, Lee PK. Management of carcinoma of the skin in solid organ
transplant recipients with oral capecitabine. Dermatol Surg. 2009; 35
(10):1567–1572
[120] Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant radiother-
apy in patients with cutaneous head and neck squamous cell carcinoma
metastatic to lymph nodes: combined treatment should be considered best
practice. Laryngoscope. 2005; 115(5):870–875
[121] Euvrard S, Morelon E, Rostaing L, et al. TUMORAPA Study Group. Sirolimus
and secondary skin-cancer prevention in kidney transplantation. N Engl J
Med. 2012; 367(4):329–339
[122] Bejar C, Maubec E. Therapy of advanced squamous cell carcinoma of the skin.
Curr Treat Options Oncol. 2014; 15(2):302–320
[123] Southwell KE, Chaplin JM, Eisenberg RL, McIvor NP, Morton RP. E ect of
immunocompromise on metastatic cutaneous squamous cell carcinoma in
the parotid and neck. Head Neck. 2006; 28(3):244–248
[124] Kwan W, Wilson D, Moravan V. Radiotherapy for locally advanced basal cell
and squamous cell carcinomas of the skin. Int J Radiat Oncol Biol Phys. 2004;
60(2):406–411
[125] Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as
first-line single-drug therapy in patients with unresectable squamous cell
carcinoma of the skin. J Clin Oncol. 2011; 29(25):3419–3426
[126] Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive
cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res.
2012; 18(5):1435–1446
[127] Brin L, Zubair AS, Brewer JD. Optimal management of skin cancer in immu-
nosuppressed patients. Am J Clin Dermatol. 2014; 15(4):339–356
[128] Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human
homolog of Drosophila patched in the nevoid basal cell carcinoma syndro-
me. Cell. 1996; 85(6):841–851
[129] Xie J, Murone M, Luoh SM, et al. Activating Smoothened mutations in spora-
dic basal-cell carcinoma. Nature. 1998; 391(6662):90–92
[130] Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candi-
date gene for the basal cell nevus syndrome. Science. 1996; 272
(5268):1668–1671
[131] Gailani MR, Ståhle-Bäckdahl M, Le ell DJ, et al. The role of the human homo-
logue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet.
1996; 14(1):78–81
[132] Aszterbaum M, Rothm an A, Johnson RL, et al. Identification of mutations
in the hum an PATCHED gene in sporadic basal cell carcinom as and in
patients with the basal cell nevus syndrom e. J Invest Dermatol. 1998;
110(6):885–888
[133] Cusack CA, Nijhawan R, Miller B, et al. Vismodegib for locally advanced basal
cell carcinoma in a heart transplant patient. JAMA Dermatol. 2015; 151
(1):70–72
[134] Zwald FO, Christenson LJ, Billingsley EM, et al. Melanoma Working Group of
The International Transplant Skin Cancer Collaborative and Skin Care in
Organ Transplant Patients, Europe. Melanoma in solid organ transplant
recipients. Am J Transplant. 2010; 10(5):1297–1304
[135] Penn I. Transmission of cancer from organ donors. Ann Transplant. 1997; 2
(4):7–12
[136] Lipson EJ, Bodell MA, Kraus ES, Sharfman WH. Successful administration of
ipilimumab to two kidney transplantation patients with metastatic mela-
noma. J Clin Oncol. 2014; 32(19):e69–e71
[137] Azijli K, Stelloo E, Peters GJ, VAN DEN Eertwegh AJ. New developments in
the treatment of metastatic melanoma: immune checkpoint inhibitors and
targeted therapies. Anticancer Res. 2014; 34(4):1493–1505
High-Risk Cutaneous Malignancies
247

248
Index
Note: Page numbers set bold or italic
indicate headings or figures,
respectively.
5
5-fluorouracil
– BCC 55, 57
– cure rates 114
– in prevention 3, 4–5, 242
– SCC 242
A
Abdel-Daim, M. 3
acitretin 5
acrochordon, clinical detection 39, 40
actinic (solar) cheilitis 25, 26, 67, 68
actinic keratosis
– chemical peels 3, 4
– chemoprevention 2
– clinical detection 25, 26
– di erential diagnosis 65
– in base of cutaneous horn 65, 67
– premalignant lesions 65, 65, 66
– prevention of 15
– primary prevention 1
adenoid cystic carcinoma
– background 106
– diagnosis 106
– epidemiology 106
– prognosis 106
– treatment 106
Akarsu, S. 3
American Academy of Dermatology 1
American Cancer Society 1
angiomata, clinical detection 33, 37,
40, 40
angiosarcoma (cutaneous)
– background 103
– biopsy 103, 103
– chemotherapy 104
– dermatopathology 228, 229
– diagnosis 103
– di erential diagnosis 103
– epidemiology 103
– prognosis 104
– radiation therapy 104
– radiation-associated 104
– staging 104
– treatment 104, 105
– workup 103
anti-VEGF Inhibitors 160
antioxidants 3
Arizona 2
arsenic exposure 26, 44
artificial intelligence (AI) machines 34,
36
atypical fibroxanthoma
– background 108
– dermatopathology 230, 231
– diagnosis 109, 109
– epidemiology 109, 109
– histology 109, 109
– malignant fibrous histiocytoma 110
– prognosis 110
– treatment 109
atypical spitzoid neoplasm 110
Australia 2
Australian Oral Nicotinamide to Reduce
Actinic Cancer (ONTRAC) trial 49
axillary node dissections 203, 204
“ No Fry Day†campaign 2
B
banal nevi 33, 37
basal cell carcinoma (BCC)
– 5-fluorouracil 55, 57
– adenoid cystic 51, 53
– arsenic exposure 26, 44
– biopsy 51
– characterization 44, 213
– chemoprevention 2
– chemoprevention, in organ trans-
plant recipients 5
– clinical detection 33, 36
– clinical presentation 49
– cryosurgery 64
– cure rates 114
– cytologic origin 43
– dermatopathology 212, 212, 213–
215
– dermoscopy 51, 54
– desmoplastic trichoepithelioma 215
– diagnosis 213
– di erential diagnosis 49, 53, 101,
106
– electrodesiccation, curettage 60
– epidemiology 23, 43
– family history as risk factor 47
– Hedgehog pathway 57–58, 58
– histologic subtypes 212
– history, physical exam 23
– imiquimod 55
– immunosuppression 45
– incidence of 43
– incidence, geographic variation
in 43
– infiltrative 24, 25, 214
– inherited disorders 47
– intralesional therapies 57
– ionizing radiation 44
– itraconazole 59
– locally advanced 57, 59, 60–61
– micronodular 50, 51–52, 214
– Mohs micrographic surgery 75–76,
76, 77, 119, 127, 128
– Mohs micrographic technique 63, 63
– morpheaform (sclerodermiform) 24,
50, 52, 62, 214
– NCCN criteria, high-risk lesions 65
– nevus sebaceous 46, 46
–– See also nevoid BCC syndrome
– nodular 23, 23, 36, 49, 50–51, 55,
213
– organ transplant recipients 244
– outcomes 75
– photodynamic therapy 56
– photosensitizing drugs 45
– pigmented 49, 50, 54
– pigmented variants 24, 24
– prevention of 48
– previous personal history 45
– radiation therapy 56, 56
– recurrence 75
– recurrence characteristics (high-
risk) 10
– recurrence characteristics (low-
risk) 9
– recurrence, risk factors 43
– risk factors 11–13, 44, 68
– selenium 5
– shave biopsy 32, 32, 51
– sunscreens and 15
– superficial 23, 24, 49, 49, 53, 55
– surgical excision 60, 62, 62, 63, 63–
64
– surgical management 59
– tanning beds 44
– targeted therapy 57, 59, 60–61
– therapeutic PUVA exposure 45
– treatment 6
– treatment selection 75
– treatment, topical 54
– UV radiation, sun exposure 44–45
– vismodegib 58–59, 163
basal cell nevus syndrome 45
Bazex syndrome 47
beta carotene 5
bevacizumab 160
biochemotherapy 159
biopsy, see specific diseases
– excisional 33, 52, 54
– fine-needle aspiration 54
– incisional 54
– lymph node 225
–– See also sentinel lymph node biopsy
– principles 31
– punch 32, 52, 54, 87, 225
– scoop shave 32, 225
– shave 32, 32, 52, 54, 86–87
– techniques 54
bleomycin 57
Bowen's disease 25, 68, 68, 69
brachytherapy 147, 148–149
BRAF inhibitors 158, 159, 159, 164
Breslow's thickness measurement 216,
224
Burmeister, B. H. 141
C
calcineurin inhibitors 149, 240, 243
capecitabine 243
carboplatin, paclitaxel regimen 159–
160
Castle Biosciences Inc. 226
CDK2NA testing 11
celecoxib 5, 48
Centers for Disease Control and Preven-
tion (CDC) 1
cetuximab 77, 163, 164, 243
Checkmate 066 Phase III trial 237
cheeks reconstruction 169, 170–173
chemical peels 3, 4
chemoprevention
– actinic keratosis 2
– BCC 2
– in organ transplant recipients 5
– principles 2
– SCC 2
chemotherapy
– dermatofibrosarcoma protuber-
ans 102
– melanoma 158
– melanoma, combination 159
– Merkel cell carcinoma 99
– SCC 77
Chen, L. L. 92
cherry angioma 37, 40, 40
CKIT Inhibitors 160
clinical detection, see under specific
cancers
Cloquet's node removal 208
COL1A1-PDGFB fusion gene 102
comparative genomic hybridization
(CGH) 221, 221
confocal scanning laser microscopy
(CSLM) 38
Criscione, V. D. 2
cryosurgery
– BCC 64
– cure rates 114
– melanoma 86
cryotherapy 2, 4
CTLA4 45
CVD regimen 159
cyclooxygenase (COX)-2 inhibitors 3, 5
cyclopamine 57–58, 58
D
dabarafenib 158–160
dacarbazine 158, 237
DecisionDx-Melanoma 226
dermatofibroma 39, 39
dermatofibrosarcoma protuberans
– background 100
– biopsy 100, 100
– chemotherapy 102
– chromosomal abnormalities 101
– clinical detection 31, 32
– dermatopathology 230, 231
– diagnosis 100, 100, 101
– di erential diagnosis 101
– epidemiology 100
– immunohistochemistry 101, 101
– Mohs micrographic surgery 101,
102
– prognosis 102
– radiation therapy 101
– staging 101
– subtypes 101
– surgical treatment 101, 102
– workup 101
dermatology 1
dermatopathology
– angiosarcoma 228, 229
– atypical fibroxanthoma 230, 231
–– See also atypical fibroxanthoma
– basal cell carcinoma 212, 212, 213–
215
– Breslow's thickness measure-
ment 216, 224
– dermatofibrosarcoma protuber-
ans 230, 231
–– See also dermatofibrosarcoma pro-
tuberans
– lymph node biopsy 225
–– See also sentinel lymph node biopsy
– malignant melanoma 218, 219–220
– Merkel cell carcinoma, see Merkel
cell carcinoma
– mitotic count 225
– overview 212
– sarcomas, cutaneous 228, 228
– SCC 213, 216–217

Index
249
dermoscopy 33, 33
diclofenac 3, 4
Dodson, J. M. 2
E
EGFR inhibitors 77, 150, 243
epigallocatechin-3-gallate (EGCG) 16
epitrochlear lymph node dissec-
tion 209, 209
erythroplasia of queyrat 26
external beam radiotherapy 146, 146,
147
eyelids facial reconstruction 172, 174–
175
F
facial reconstruction
– cheeks 169, 170–173
– eyelids 172, 174–175
– forehead 168, 169
– lips 173, 176–181
– nose 179, 182–190
– overview 168
familial atypical multiple mole melano-
ma syndrome (FAMMS) 11, 235
Ferguson-Smith disease 28
fibroxanthoma, atypical, see atypical fi-
broxanthoma
FISH 221, 221, 221, 222
G
gefitinib 150
Go Sun Smart Health Communication
Campaign 13
Gorlin's syndrome, see nevoid BCC syn-
drome
green tea 16
groin dissection 205, 205, 206–207
H
Haigh, P. I. 88
hats 16
Hedgehog inhibitors 163
Hedgehog pathway 57, 58
HIV/AIDS 236–238, 238
HPV vaccine 70
I
iliac, obturator node dissection 208
imatinib mesylate 102, 160
imiquimod
– BCC 55
– cure rates 114
– in prevention 3, 4
immune checkpoint inhibitors 77
immune surveillance 236
immunosuppression
– in high-risk cutaneous malignan-
cies 236
– in organ transplant recipients 238
– medications 240
– nonmelanoma skin cancer 149, 240
– radiation therapy and 149
– SCC 45, 70
immunotherapy 160, 161
indocyanine green 192
inflammation, chronic 71, 71
inguinofemoral node (groin) dissec-
tion 205, 205, 206–207
intensity modulated radiotherapy 147
interferon alfa-2b (IFNα2β) 159, 162
interferons 57
Intergroup Melanoma Trial 88
interleukin-2 159, 160
intralesional therapies 57
ionizing radiation 44
ipilimumab 158, 160, 161, 161, 162,
164
isosulfan dye 89
itraconazole 59
J
Jiang, S. B. 4
K
Kaposi's sarcoma 101, 103, 240
keratoacanthoma 26, 27, 32, 32
Krawtchenko, N. 2–3
L
laser ablation 4, 4
leiomyoma 101
leiomyosarcoma (cutaneous)
– background 104
– diagnosis 104
– epidemiology 104
– prognosis 106
– treatment 104
lentigo maligna 29, 29, 32, 32, 119,
126, 222
lentigo maligna melanoma 29, 29, 223,
223
lentigo, lentigo simplex 38, 39
leukoplakia 26, 27, 65, 67
lips reconstruction 173, 176–181
Lubritz, R. R. 3
lymph node biopsy 225
– See also sentinel lymph node biopsy
lymphadenectomy 90, 90
lymphoscintigraphy
– performance 194
– principles 192, 193
– tim ing 194
M
malignant fibrous histiocytoma 110
Manyam, B. V. 149
Marjolin's ulcer 71, 71
McCarthy, W. H. 12
McMasters, K. M. 91
medications
– consolidation of 12, 12
– immunosuppressive 240
– photosensitizing 45
– with reported photosensitivity 12
medulloblastoma 46, 57
MEK inhibitors 158, 159
MelaFind 36
melanoma
– acral, acral lentiginous 30, 30, 223,
223
– adjuvant therapy 162
– AJCC TNM criteria 9
– amelanotic 30
– biopsy 225
– characterization 235
– chemotherapy 158
– clinical detection 29, 38
– combination chemotherapy 159
– comparative genomic hybridiza-
tion 221, 221
– cure rates 114
– desmoplastic 30, 31, 92, 141, 224,
224
– diagnostic aids in 221
– di erential diagnosis 49, 51, 101,
103
– dysplastic nevus 220
– epidemiology 1, 86, 158
– family history of 11
– FISH 221, 221, 221, 222
– follow-up 10, 11
– histologic subtypes 222
– HIV+patients 238
– hypertherm ia, radiation therapy
combination 154
– immunohistochemistry 222
– in situ 29, 34, 87, 87
– in-transit, interval nodes signifi-
cance 91
– invasive 35
– lentigo maligna 29, 29, 34, 222
– lentigo maligna melanoma 29, 29,
34, 223, 223
– malignant, dermatopathology 218,
219–220
– median onset 11
– metastatic 158
– metastatic, surgery for 163
– Mohs micrographic surgery 119,
126
– mucosal 30
– Myriad MyPath 222
– node-negative 89–90
– nodular 30, 30, 34, 35, 141, 223
– organ transplant recipients 244
– pattern analysis 33–34, 34–35
– pediatric 93
– prevention of 15
– primary prevention 1
– prognostic features 226
– radiation therapy, indications 141,
141, 142–144
– referral 10
– risk factors 6–7, 86
– second opinion requests 220–221
– Spitzoid 110, 219
– structured reporting protocol,
pathologic data elements 224
– superficial spreading 29, 29, 34, 220,
222
– surgical treatment, see surgical treat-
ment (melanoma)
– treatment 9
Merkel cell carcinoma
– background 96
– biopsy 96, 97
– chemotherapy 99
– clinical detection 31, 31
– dermatopathology 227, 227
– diagnosis 96, 96
– di erential diagnosis 51
– epidemiology 96, 240
– interferons 99
– lymph node dissection 99
– lymph nodes 97–98
– MCV positive 99
– micrometastases 98
– oncogenic viruses 238
– polyomavirus 97
– prognosis 100
– prognostic features reported 227,
228
– radiation therapy 99
– sentinel lymph node biopsy 98, 98–
99, 100, 228
– staging 98
– surgical treatment 98, 98, 99
– systemic therapy 158
– workup 97
Merkel, F. 96
metastasectomy 163–164
microcystic adnexal carcinoma
– background 107
– biopsy 108, 108
– diagnosis 107, 108
– epidemiology 107
– histology 108
– prognosis 108
– treatment 108
Miller, D. D. 12
minimally invasive groin dissec-
tion 207, 208
mitotic count 225
Mohs micrographic surgery
– advantages of 114, 117
– appropriate use criteria 116, 120
– case presentations 127, 128–130,
130, 131
– complications 124
– cost-e ective care 120
– cure rates 114, 118
– dermatofibrosarcoma protuber-
ans 101, 102
– geometric staged excision 126
– histologic examination/interpreta-
tion 124
– horizontal (Mohs) sectioning 117,
117, 118
– indications, contraindications 117,
118, 119–120
– initial (A) layer 123
– integration of 127
– intraoperative considerations 121
– limitations of 92
– mapping 122–123, 124
– melanoma, lentigo maligna 119, 126
– modifications of 119, 126
– overview 114
– patient education 121
– photography 121
– postoperative evaluation 124
– preoperative assessment 120
– rapid stains 119, 126, 127
– recurrence risk by body area 114,
116
– SCC 75–76, 76, 77
– single section method 126
– slow Mohs 126
– surgical margins tissue processing
techniques 114
– technique 120, 121–123
– tissue sparing 114, 115
– training 114
– tum or extirpation 121, 122–123
– vertical (bread loafing) section-
ing 116, 117
– wide excision 127
– wound management 122–123, 124,
125–126

Index
250
Mohs, F. 77
mole map, log 8
mTOR inhibitors 149, 241, 243
Multicenter Selective Lymphadenec-
tomy Trial-I (MSLT-1) 89–90, 163
multiple self-healing squamous epithe-
lioma (MSSE) 28
Myriad MyPath 222
N
National Council on Skin Cancer Pre-
vention 1
nevoid BCC syndrome
– characterization 235
– clinical features 47, 47, 47, 48
– diagnosis of 47, 47
– follow-up 11
– genetic testing 11
– vismodegib 59
nevus sebaceous BCC 46, 46
nicotinamide 49
nivolumab 161
nonmelanoma skin cancer, see basal cell
carcinoma (BCC), squamous cell car-
cinoma (SCC)
– acitretin 5
– biology 239, 239
– COX-2 in pathogenesis of 5
– demographics 240
– epidemiology 1, 23, 239
– follow-up 10, 10
– immunosuppressed patients 149
– immunosuppressive medica-
tions 240
– median onset 11
– personal history as risk factor 71
– previous personal history 45
– primary prevention 1
– referral 9
– risk factors 2, 12–13, 240
– systemic retinoids 5
– systemic therapy 163
– treatment 6
nose reconstruction 179, 182–190
O
O'Brien, C. J. 141
oncogenic viruses 237
oncolytic virus immunotherapy 162
operative lymphadenectomy
– axillary node dissections 203, 204
– Cloquet's node removal 208
– complications of 203
– epitrochlear lymph node dissec-
tion 209, 209
– general considerations 197
– iliac, obturator node dissection 208
– inguinofemoral node (groin) dissec-
tion 205, 205, 206–207
– minimally invasive groin dissec-
tion 207, 208
– modified radical neck dissec-
tion 200, 200, 201–202
– neck dissection 198, 199
– overview 192
– parotidectomy, neck dissection 202
– popliteal lymphadenectomy 209,
210
– posterior cervical chain dissec-
tion 203
– preoperative workup 197
– sartorius flap 207, 208
– selective nodal dissections 203
– SNLB, see sentinel lymph node biop-
sy
– terminology 199
organ transplant recipients
– BCC 244
– chemoprevention in 5
– immunosuppression in 149, 236,
238, 240
– melanoma 244
– SCC 239, 241, 242
orthovoltage X-rays 146, 146
outdoor workers, prevention in 12
P
parotidectomy, neck dissection 202
patient education 241
PD-1, PDL-1 inhibitors 77, 158, 161,
164
pegylated IFN?2? 162
pembrolizumab 161
photoaging 15
photoallergic reactions 12, 14
photodynamic therapy 3, 4, 56, 243
photosensitizing drugs 45
pigmented neoplasms 33, 33, 34
pilots, flight personnel, prevention
in 13
pleomorphic sarcoma (undi erenti-
ated) 110
Pool Cool program 2
popliteal lymphadenectomy 209, 210
prevention
– 5-fluorouracil 3, 4–5, 242
– antioxidants 3
– chemical peels 3, 4
– chemoprevention 2
– chemoprevention, in organ trans-
plant recipients 5
– community outreach 2
– cryotherapy 2, 4
– cyclooxygenase-2 inhibitors 3, 5
– diclofenac 3, 4
– dietary modifications 5
– follow-up 10
– green tea 16
– hats 16
– imiquimod 3, 4
– in high-risk groups 12
– in outdoor workers 12
– in pilots, flight personnel 13
– laser ablation 4, 4
– medications, consolidation of 12, 12
– overview 1
– patient education 241
– photodynamic therapy 3, 4
– preventive treatment 2
– primary prevention 1, 1
– protective clothing 16
– referral 9
– secondary prevention 6
– shade 16
– sun protection methods 13
– sun-safety curriculums 2
– sunglasses 16
– systemic retinoids 5
– tanning beds 13
– treatment 6
protective clothing 16
psoralen plus UV-A phototherapy (PU-
VA) 12, 45
PTCH1, PTCH2 45–46, 57, 58
pyogenic granuloma 40, 41
R
radiation therapy, see specific diseases
– brachytherapy 147, 148–149
– cure rates 114
– cutaneous melanoma, indications
for 141, 141, 142–144
– definitive, indications for 134, 134,
135, 135–137, 141
– dermatofibrosarcoma protuber-
ans 101
– dose, fractionation paradigms 142,
145
– electron energies 146, 146
– external beam radiotherapy 146,
146, 147
– hypertherm ia and, for melano-
ma 154
– immunosuppressed patients 149
– in organ transplant recipients 149
– indications 134
– intensity modulated radiother-
apy 147
– lymph node metastasis 136
– Merkel cell carcinoma 99
– orthovoltage X-rays 146, 146
– overview 134, 134
– palliative, for metastatic disease 150,
151–153
– photon energies 147, 147
– postoperative, indications for 136,
136, 137, 138, 139, 139–141, 141,
142
– recurrent NMSC 154, 154–155
– surface mold brachytherapy 148,
148–149
– systemic therapy concurrent 150
– techniques, targeting 145
reconstructive surgery, see facial recon-
struction
resources 1
rhabdomyosarcoma 46, 57
Rombo syndrome 47
S
sarcoidosis 101
sarcomas, cutaneous 228, 228
sartorius flap 207, 208
scalp, erosive pustular dermatitis
of 40, 41
sebaceous carcinoma
– background 106
– diagnosis 106, 107
– epidemiology 106
– prognosis 107
– staging 107
– treatment 107
sebaceous hyperplasia 39, 40
seborrheic keratoses 33, 37–38, 38
selenium 5
sentinel lymph node biopsy
– 10% rule 195
– atypical spitzoid neoplasm, spitzoid
melanoma 111
– complications 196
– desmoplastic melanoma 92
– drainage patterns 194, 194
– frozen sections 196
– head, neck region considera-
tions 196
– lymph node metastasis 136
– lymphoscintigram performance 194
– lymphoscintigram timing 194
– lymphoscintigraphy 192, 193
– Merkel cell carcinoma 98, 98–99,
100
– node identification di culties 195,
195, 196–199
– performance of 194
– SCC 77, 218, 218
– surgical treatment (melanoma) 88,
90
– technical aspects 192
– true node identification 195
shade 16
SIAscope 38
sirolimus 149, 243
skin self-examinations (SSE) 6, 7–8
skin tags, clinical detection 39, 40
skin, characterization 43
small cell lung carcinoma 96
Smolewski, S. A. 3
Smoothened oncogene 57
solar cheilitis, see actinic (solar) cheili-
tis
solar lentigines 33, 37
Spitz nevi
– background 110
– diagnosis 110, 110
– epidemiology 110
– sentinel lymph node biopsy 111
– treatment, prognosis 111
squamous cell carcinoma (SCC), see ac-
tinic keratosis
– 5-fluorouracil 242
– acantholytic 216
– acitretin 5
– actinic (solar) cheilitis 25, 26, 67, 68
– age of onset 44
– aggressiveness, metastases 74, 77
– AJCC staging system 72–73
– arising from SCC in situ 26, 27
– Bowen's disease 25, 68, 68, 69
– Bowenoid 216
– Breslow's thickness measure-
ment 216, 224
– characterization 64
– chemoprevention 2
– chemoprevention, in organ trans-
plant recipients 5
– chemotherapy 77
– cure rates 114
– cutaneous SCC 43, 216–218
– cytologic origin 43
– dermatopathology 213, 216–217
– di erential diagnosis 65, 106
– EGFR inhibitors 77
– electrodesiccation, curettage 60
– epidemiology 24, 43, 158
– erythroplasia of queyrat 26
– family history as risk factor 47, 72
– high-risk, identification of 72, 72,
73, 74
– histologic grading 214
– history, physical exam 25
– HIV+patients 238
– HPV-induced 64, 70
– imaging 74
– immune checkpoint inhibitors 77

Index
251
– immunosuppression 45, 70
– in base of cutaneous horn 65, 67
– in situ 25
– inflammation, chronic 71, 71
– inherited disorders 70
– keratoacanthoma 26, 27, 217
– leukoplakia 26, 27, 65, 67
– long-term management, follow-
up 78
– lymphatic system metastases 198
– management approach 74
– Mohs micrographic surgery 75–76,
76, 77, 119, 130, 130, 131
– NCCN classification 72–73
– organ transplant recipients 241, 242
– outcomes 75
– perineural invasion 216, 218
– personal history as risk factor 71
– positive margin indicators 218, 218
– premalignant lesions 64
– prevention of 15
– previous personal history 45
– radiation therapy 74, 77, 149–150,
243
– recurrence 75
– recurrence characteristics (high-
risk) 10
– recurrence characteristics (low-
risk) 9
– recurrence, metastases risk 218
– risk factors 12–13, 44, 68
– sarcomatoid, epithelioid 217
– sarcomatoid, spindle cell 217
– selenium 5
– sentinel lymph node biopsy 77, 218,
218
– shave biopsy 32, 32
– subtypes 214
– surgical management 75
– tanning beds 71
– topical therapy 74
– treatment selection 75
– UVexposure 70, 72
– verrucous 28, 28, 216
Stewart-Treves syndrome 103, 104
Strom, T. 92
sun protection methods 13
Sunbelt Melanoma Trial 89, 91
sunburns as risk factor 2, 13
sunglasses 16
sunscreen
– BCC and 15
– characterization 14, 14
– health benefits 15
– photoaging 15
SunWise program 2, 13
surface mold brachytherapy 148, 148–
149
surgical treatment (melanoma)
– biopsy 86
– cryosurgery 86
– cure rates 114
– desmoplastic melanoma 92
– electrodessication 86
– epidemiology 86
– immediate vs. delayed reconstruc-
tion 91
– invasive, thin, intermediate thick-
ness 87, 87
– lymph node evaluation 88
– lymphadenectomy 90, 90
– lymphoscintigraphy, preopera-
tive 91
– margins of excision 87
– melanoma in situ 87, 87
– Mohs micrographic surgery 75–76,
76, 77, 92
– orientation of incision 86
– pediatric melanoma 93
– sentinel lymph node biopsy 88, 90
– thick melanomas 88
Swedish Melanoma Study Group Tri-
als 87
systemic retinoids 5, 243
systemic therapy, see specific drugs by
name
– anti-VEGF Inhibitors 160
– BRAF inhibitors 158, 159, 159, 164
– CKIT Inhibitors 160
– immunotherapy 160, 161
– interleukin-2 159, 160
– MEK inhibitors 158, 159
– melanoma 158
– melanoma, adjuvant therapy 162
– nonmelanoma skin cancer 163
– oncolytic virus immunotherapy 162
– overview 158, 165
– PD-1, PD-L1 Inhibitors 77, 158, 161,
164
– surgical implications 163
– toxicities, surgical management
of 164
T
T cell checkpoint inhibitors 161
talimogenela herparepvec (T-VEC) 162
tanning beds 13, 44, 71
targeted therapy 159
tattoo ink as dye 89
temozolomide 158
Thai, K. E. 3
The Skin Cancer Foundation 1
Thomas, J. M. 88
titanium dioxide 14
trametinib 158–160
U
UV radiation, sun exposure 44–45, 70,
72, 237
V
vemurafenib 158–159
vismodegib 57–59, 163
voriconazole 12
W
Wasif, N. 92
X
xeroderma pigmentosum (XP)
– as risk factor 47, 70
– characterization 235
– follow-up 11
– genetic testing 12
Y
Yamamoto, M. 90
Z
Zager, J. S. 91
zinc oxide 14
Zitelli, J. A. 75

(Trang không có chữ)