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

Clinical trial data have confirmed the utility of MelaFind to
aid detection of melanoma. The pivotal trial examined MelaFind
use at seven di erent sites within the United States on 1,831
lesions from 1,383 patients.18 In the study, MelaFind showed
sensitivity of 98.4% and specificity of 9.9% for detection of mela-
noma. This was compared with values of 78% sensitivity and
3.7% specificity for clinician standard examinations with or
without the aid of a dermatoscope. The biopsy ratio (i.e., the
number of normal or benign lesions biopsied for detected mela-
noma or high-grade dysplastic nevus) was 7.6. This is compared
to varied reports of biopsy ratio for unaided clinicians from 1:5
to 1:500, and similar to those values reported for experienced
dermatologists with demoscopy.19,20 MelaFind has the potential
to enable clinicians to detect more melanoma while sparing
more benign lesions, limiting unneeded procedures and poten-
tially decreasing overall health care costs.
2.8.2 Confocal Microscopy and Other
Nonstandard Assays and Techniques
Confocal Scanning Laser Microscopy
Confocal scanning laser microscopy (CSLM) is yet another non-
invasive imaging tool garnering increased attention in both the
clinical and research setting. CSLM captures in vivo horizontal
images of skin from epidermis to papillary dermis in real time.
CSLM works by focusing a laser beam at a point on the skin.
Light is reflected back through an aperture on the device. There
are two modes, reflectance and fluorescence. In the clinical set-
ting, CSLM utilizes the reflectance mode, which takes advantage
of the inherent variability in reflectance patterns of various skin
organelles and appendages. Melanin granules have high refrac-
tive index. This allows visualization of the concentration and
uniformity of melanin concentration and melanocytes.21 Hemo-
globin can also be visualized, allowing for interpretation of
blood flow. Reflectance confocal microscopy (RCM) uses a near-
infrared 830-nm laser, which provides an imaging depth of 250
to 300 µm in normal skin, allowing visualization into the super-
ficial dermis.
Clinical trials show that CSLM has excellent sensitivity
(88.15–97.5%) and specificity (83–99%) for determining mela-
noma or melanoma in situ from benign melanocytic lesions
when utilized by a trained operator.22,23,24 While automated
models are in development, CSLM still relies on clinician inter-
pretation of image output in order to make a decision to biopsy.
SIAscope
Similar to MelaFind, spectrophotometric intracutaneous analy-
sis (SIA) utilizes images captured using a range of radiation
from 400 to 1,000 nm to aid in the clinical diagnosis of mela-
noma. The clinical device is aptly named the SIAscope (Biocom-
patibles, Farnham, Surrey). SIAscope is used by centering the
handset on a pigmented lesion of maximum size of 24 mm.
Eight narrowband images are obtained of skin lesions in vivo,
and software analyzes cutaneous chromophores such as mela-
nin, blood, and collagen within the papillary dermis. Informa-
tion can be gathered regarding the position of melanin relative
to the dermoepidermal junction, that is, allowing a clinician to
assess melanocyte invasion in real time. Images obtained by
SIAscope are returned to clinical as SIAgraphs, which contain
detailed information of dermal components for clinicians.25
Clinical trials demonstrate that siascopy may aid in clinical
detection of melanoma when one or more characteristic pat-
terned features are identified. For example, identification of
dermal melanin, blood displacement with blush (defined as
central blood displacement with peripheral blood increase
compared to surrounding normal skin), and lesion size greater
than or equal to 6 mm along predicted diagnosis of melanoma
with an 82.7% sensitivity and 80.1 sensitivity.25 Presence of
deep dermal melanin, used as a single feature, predicted diag-
nosis of melanoma with 96.2% sensitivity and 56.8% specificity
in a test set of 348 pigmented lesions.
2.9 Common Look-Alikes
2.9.1 Seborrheic Keratoses
Over one-half of all adult patients will have at least one sebor-
rheic keratosis (SK), a benign lesion commonly described as a
waxy-brown, “stuck-on,” or “barnaclelike” hyperkeratotic pap-
ule ( Fig. 2.28). SKs have a predilection for the trunk, but may
be ubiquitous. Lesions are symmetric, and often oval-shaped, as
they stretch along skin tension lines. Variants include flatter
macular seborrheic keratoses of the face and head, stucco kera-
toses—multiple SKs of the lower limbs, and dermatosis papu-
losa nigra—a more heavily pigmented variant in darker skinned
individuals. Seborrheic keratoses should be clinically recog-
nized, and biopsy or excision avoided. Di erential diagnosis
includes pigmented lesions or common warts.
2.9.2 Lentigo
Lentigo or lentigo simplex represents a tan or light-brown
m acule on sun-exposed areas such as face, dorsal hands, and
forearm s. Pigm ent is usually even, and borders are sharp
( Fig. 2.29). These lesions represent acquired melanocytic
Fig. 2.28 Numerous seborrheic keratoses across the upper back of an
elderly male.
Clinical Detection of Skin Cancer
38

hyperplasia. Patients are typically over 30 years of age, fair-
skinned, and have background UV dam age.
2.9.3 Dermatofibroma
A dermatofibroma (DF) is a small (<1 cm) symmetric papule or
nodule usually found on the lower extremities of females. DFs
may appear brown or pink with color accentuated on the
periphery of the lesion ( Fig. 2.30). When manually pinched,
DFs have a characteristic central depression; this is known as
the “dimple sign.” These lesions may itch or sting given that
they are made of proliferating fibroblasts and may encompass
cutaneous nerves. DFs are thought to be the result of local
minor trauma induced by acts such as shaving. These lesions
are benign with no malignant potential.
2.9.4 Acrochordon
More commonly known as skin tags, acrochorda are commonly
seen in patients over the age of 40 in areas of skin friction such
as the groin, axilla, or neck crease ( Fig. 2.31).
2.9.5 Sebaceous Hyperplasia
Sebaceous hyperplasia manifests as a small waxy or greasy yel-
low papule, usually on the central face. These lesions are small,
commonly less than 5 mm in size. Lesions may have slight cen-
tral dell or depression ( Fig. 2.32). They may be grouped
(Fig. 2.33). Lesions of sebaceous hyperplasia are commonly
confused for BCC.
Fig. 2.29 Multiple prominent facial lentigines.
Fig. 2.30 (a, b) Dermatofibroma. Two examples of shiny brown or pink papules commonly on the lower extremities of females.
Clinical Detection of Skin Cancer
39

2.9.6 Cherry Angioma
Angiomata represent small bright red papules commonly of the
trunk. Thrombosed angiomata appear purple (Fig. 2.34).
Patients with one or more cherry angioma commonly have a
strong family history of such lesions. These lesions will blanch
when pressure is applied with a transparent glass slide.
2.9.7 Pyogenic Granuloma
A pyogenic granuloma is a rapidly growing red to purple papule
that grows commonly in the head and neck, extremities, or oral
mucosa (Fig. 2.35). These lesions commonly bleed. Pyogenic
granulomas are common in young adults, and overrepresented
in pregnant females.
2.9.8 Erosive Pustular Dermatitis of
Scalp
There are many chronic inflammatory conditions of the skin
that may mimic malignancy. Erosive pustular dermatitis of the
scalp develops as enlarging erosive and ulcerative plaques with
associated pus and scale crust (Fig. 2.36). Patients are typi-
cally older, may have associated solar damage, and can be mis-
taken for impetiginized SCC or multiple AKs of the scalp.
Fig. 2.31 Multiple acrochorda in the right axillary vault of a middle-
aged African American male.
Fig. 2.32 Sebaceous hyperplasia. Lesions are commonly yellow or pink
and display a central dell or depression.
Fig. 2.33 Grouped sebaceous hyperplasia.
Fig. 2.34 Thrombosed angioma.
Clinical Detection of Skin Cancer
40

Fig. 2.36 (a) Erosive pustular dermatosis of the scalp with overlying scale crust. (b) After removal of scale crust.
Fig. 2.35 (a) Pyogenic granuloma arising on a distal digit.(b) Large pyogenic granuloma near the lateral oral commissure of an infant.
Clinical Detection of Skin Cancer
41

References
[1] Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmela-
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(3):283–287
[2] Quaedvlieg PJ, Tirsi E, Thissen MR, Krekels GA. Actinic keratosis: how to
di erentiate the good from the bad ones? Eur J Derm atol. 2006; 16
(4):335–339
[3] Browne F, O’Connell M, Merchant W, Potts E, Fenn C, Stables G. Spontaneous
resolution of a giant keratoacanthoma penetrating through the nose. Clin Exp
Dermatol. 2011; 36(4):369–371
[4] El-Khayat RH, McGrath C, Walsh MY, Ferguson M, Hoey SE. Spontaneous res-
olution of keratoacanthoma centrifugum marginatum. Clin Exp Dermatol.
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[5] Nofal A, Assaf M, Ghonemy S, Nofal E, Yosef A. Generalized eruptive keratoa-
canthoma: a diagnostic and therapeutic challenge. Int J Dermatol. 2015; 54
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[6] Swetter SM, Boldrick JC, Jung SY, Egbert BM, Harvell JD. Increasing incidence
of lentigo maligna melanoma subtypes: northern California and national
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[7] Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol. 2009;
27(1):3–9
[8] Bradford PT, Anderson WF, Purdue MP, Goldstein AM, Tucker MA. Rising mel-
anoma incidence rates of the trunk among younger women in the United
States. Cancer Epidemiol Biomarkers Prev. 2010; 19(9):2401–2406
[9] Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carci-
noma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol.
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[10] Carli P, de Giorgi V, Chiarugi A, et al. Addition of derm oscopy to conventional
naked-eye examination in melanoma screening: a randomized study. J Am
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[12] Argenziano G, Soyer HP, Chimenti S, et al. Dermoscopy of pigmented skin
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[13] Pehamberger H, Steiner A, Wol K. In vivo epiluminescence microscopy of
pigmented skin lesions. I. Pattern analysis of pigmented skin lesions. J Am
Acad Dermatol. 1987; 17(4):571–583
[14] Braun RP, Rabinovitz HS, Oliviero M, Kopf AW, Saurat JH. Dermoscopy of pig-
mented skin lesions. J Am Acad Dermatol. 2005; 52(1):109–121
[15] Pehamberger H, Binder M, Steiner A, Wol K. In vivo epiluminescence micro-
scopy: improvement of early diagnosis of melanoma. J Invest Dermatol. 1993;
100(3):356S–362S
[16] Longo C, Lallas A, Kyrgidis A, et al. Classifying distinct basal cell carcinoma
subtype by means of derm atoscopy and reflectance confocal microscopy. J
Am Acad Dermatol. 2014; 71(4):716–724.e1
[17] Patel JK, Konda S, Perez OA, Amini S, Elgart G, Berm an B. Newer technologies/
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(6):617–631
[18] Monheit G, Cognetta AB, Ferris L, et al. The performance of MelaFind: a pro-
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[19] Kupetsky EA, Ferris LK. The diagnostic evaluation of MelaFind multi-spectral
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[20] Terushkin V, Warycha M, Levy M, Kopf AW, Cohen DE, Polsky D. Analysis of
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[21] Meyer LE, Otberg N, Sterry W, Lademann J. In vivo confocal scanning laser
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[22] Gerger A, Koller S, Kern T, et al. Diagnostic applicability of in vivo confocal
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[23] Gerger A, Hofmann-Wellenhof R, Langsenlehner U, et al. In vivo confocal laser
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[24] Langley RG, Walsh N, Sutherland AE, et al. The diagnostic accuracy of in vivo
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[25] Moncrie M, Cotton S, Claridge E, Hall P. Spectrophotometric intracutaneous
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2002; 146(3):448–457
Clinical Detection of Skin Cancer
42

3 Treatment of Squamous and Basal Cell Carcinoma of the
Skin
Rogerio I. Neves and Morgan Brgoch
3.1 Introduction
Basal cell and squamous cell skin cancers, collectively known as
nonmelanoma skin cancers (NMSCs), are the most common
cancer in the United States. An estimated 5 million cases of
NMSC are diagnosed annually; this exceeds the incidence of all
other cancers combined.1,2 In the United States alone, the diag-
nosis and treatment of NMSCs has increased dramatically with
a growth rate of 77% over the past two decades. The average
annual number of adults treated for skin cancer increased from
3.4 million in 2002–2006 to 4.9 million in 2007–2011. During
this period, the average annual total cost for skin cancer
increased from $3.6 billion to $8.1 billion, representing an
increase of 126.2%, while the average annual total cost for all
other cancers increased by 25.1%. During 2007–2011, nearly
5 million adults were treated for skin cancer annually,
with average treatment costs of $8.1 billion each year, about
$4.8 billion for NMSCs and $3.3 billion for melanoma.2,3 While
surveillance and diagnosis has continued to improve, the inci-
dence of this common malignancy also appears to be rising
rapidly.4
Basal cell carcinomas (BCCs) are roughly four to five times
more common than squamous cell carcinomas (SCCs). More
than 2.8 million new cases of BCC are diagnosed each year in
the United States alone, and are estimated to result in more
than 3,000 deaths.5,6,7 Although rarely metastatic, BCC and SCC
can produce substantial local invasion and destruction along
with disfigurement and may involve extensive areas of underly-
ing soft tissue, cartilage, and bone.
Cutaneous squamous cell carcinoma (cSCC) is the second
most common NMSC worldwide. While most of these lesions
can be successfully managed with excision, there is a subset of
lesions that metastasize, leading to severe morbidity and mor-
tality. While small, the number of cSCCs that metastasize has
been compared to the metastatic rate of renal and oropharyn-
geal carcinomas.8
The skin is a complex organ made up of multiple cell types
and many of these cell types can undergo malignant transfor-
mation at various points in their di erentiation, leading to
tumors with distinct histology and dramatically di erent bio-
logical behaviors, such as SCC and BCC. The outer layer or epi-
dermis is made primarily of keratinocytes but has several other
minor cell populations. The bottom layer is formed of basal ker-
atinocytes abutting the basement membrane. The basement
membrane is formed from products of keratinocytes and der-
mal fibroblasts, such as collagen and laminin, and is an impor-
tant anatomical and functional structure. As the basal
keratinocytes divide and di erentiate, they lose contact with
the basement membrane and form the spinous cell layer, the
granular cell layer, and the keratinized outer layer or stratum
corneum.
The true cytologic origin of BCC remains in question; how-
ever, BCC and basal cell keratinocytes share many histologic
similarities. Alternatively, the outer root sheath cells of the hair
follicle have also been proposed as the cell of origin for BCC.9,10
This is suggested by the fact that BCCs occur predominantly on
hair-bearing skin. BCCs rarely metastasize but can invade tissue
locally or regionally, with a potential for perineural invasion
and rapid spread. A tendency for superficial necrosis in the cen-
ter in the lesion has resulted in the characteristic name “rodent
ulcer,” frequently used to describe such growths.
Similarly, debate remains about the origin of SCC; however,
the leading hypothesis illustrates the derivation of cutaneous
SCC from epidermal stem cells associated with the hair fol-
licles.11 Avariety of tissues, such as lung and uterine cervix, also
give rise to SCC, with varying characteristics depending on the
tissue source. SCC derived from di erent anatomic locations
can have moderately di ering aggressiveness and expected
clinical course; for example, SCC from glabrous (smooth, hair-
less) skin frequently has a lower metastatic rate than SCC aris-
ing from the vermillion border of the lip or from scars.12
Estimates of the incidence of BCC are imprecise, given there
is currently no central registry that collects data on BCC occur-
rence. Lower estimates cited by The American Cancer Society
estimates that more than 2 million NMSCs were treated in the
United States in 2006. However, a population-based study esti-
mated a higher number of lesions, reporting that approximately
3.5 million NMSCs were treated in the United States during the
same year.1 Additionally, several incidence-based mathematical
models support a higher prevalence of NMSC in the United
States.13 According to the model, approximately 13 million
white non-Hispanic individuals living in the United States in
2007 may have had a personal history of at least one NMSC.
Individuals with a history of BCC are at increased risk for sub-
sequent lesions. Approximately 40% of patients who have had
one BCC will develop another lesion within 5 years.14,15 Multi-
ple epidemiologic observations provide insights into the etiol-
ogy of BCC. Namely, BCC is particularly common in Caucasians
and very uncommon in blacks and other dark-skinned popula-
tions. In white populations in the United States, the incidence
of BCC has increased by more than 10% per year, and the life-
time risk of developing a BCC is estimated at 30%.16,17,18 An
increasing incidence has also been noted in other countries,
such as Canada, Finland, and Australia,19,20,21 with evidence
of increasing incidence of aggressive-growth histologic
subtypes.22
There is notable geographic variation in incidence, likely sec-
ondary to environmental exposures and protection strategies.
States closer to the equator, such as Hawaii and California, have
an incidence of BCC at least twice that of the Midwestern United
States.23,24,25 There are also prominent global variations in inci-
dence. Northern European countries, such as Finland, have an
incidence one-fourth that of the Midwestern United States ver-
sus Australia where rates are 40 times that of Finland.19,26
Men have a 30% higher incidence than women and also a
higher incidence of superficial type BCC.19,23,27,28 The incidence
of BCC increases with age; persons aged 55 to 75 have about a
100-fold higher incidence of BCC than those younger than 20.29
Treatment of Squamous and Basal Cell Carcinoma of the Skin
43

Although an aging population with higher life expectancies
may account for part of the increasing incidence of BCC, the
incidence of BCC among Americans younger than 40 also
appears to be increasing, particularly among women.4
In the United States, the average age of onset of cutaneous
SCC is 65 years;30 however, there are increasing reports of
patients as young as 20 to 30 years of age in regions of higher
ultraviolet (UV) exposure such as Florida and southern Califor-
nia. There is a predilection for males, but the incidence of SCC
originating on the legs is greater in females. Factors that
increase the risk for SCC include Fitzpatrick skin types I and II,
outdoor occupations such as farming and construction work,
and exposure to human papillomavirus (HPV) types 16, 18, and
31.31
Exposure to UV radiation and sunlight is the greatest risk fac-
tor, as illustrated in studies showing a direct correlation
between psoralen plus ultraviolet A light (PUVA) exposure and
the incidence of SCC.32,33,34,35 In this study, the relative risk for
developing SCC in patients with 350 to 450 PUVA treatments
compared with less than 50 treatments was 6.01.13,34 Treatment
with PUVA increases the risk for SCC by two mechanisms,
which refer to, respectively, its mutagenic e ects and its immu-
nosuppressive e ects.
Overall, SCC is uncom m on in dark-skinned individuals, but
it rem ains the most com m on cutaneous cancer in African-
Am ericans. In such individuals, the cancer usually occurs in
areas that are not sun exposed.36 Darkly pigm ented skin
possesses greater am ounts of melanin in the epidermis,
w hich partially protects against the carcinogenic e ects of
UV light. As a result, sun exposure is a less com mon etiol-
ogy. As in the overall population, SCC in darker skin is often
preceded by the developm ent of actinic keratosis (AK).37,38
BCC is a common skin cancer arising from the basal layer of
epidermis and its appendages. These tumors have been referred
to as “epitheliomas” because of their low metastatic potential.
However, the term carcinoma is appropriate, since they are
locally invasive, aggressive, and destructive of skin and the sur-
rounding structures including bone.
3.2 Risk Factors for Basal Cell
Carcinoma
3.2.1 Ultraviolet Radiation
Sun exposure is the most important environmental cause of
BCC, and most risk factors relate directly to a person’s sun expo-
sure habits or susceptibility to solar radiation. These risk factors
include having fair skin, light-colored eyes, red hair, northern
European ancestry, older age, childhood freckling, and an
increased number of past sunburns.39,40,41
The type, quantity, and timing of sun exposure associated
with an increased risk of BCC are not clearly defined. Childhood
sun exposure appears to be more important than exposure dur-
ing adult life.40,42 In a Canadian case control study that included
226 men with BCC and 406 age-matched controls, the develop-
ment of BCC was strongly correlated with childhood and ado-
lescent sun exposure but not cumulative or recent sun
exposure.42 In other studies, however, adult sun exposure also
was a risk factor for BCC.41 It has been estimated that aggressive
sun protection before the age of 18 years could reduce the num-
ber of NMSCs by almost 80%.43 Several trials provide evidence
that sunscreen use decreases the incidence of SCCs and that
there are no adverse e ects from sunscreen use.44,45 However, a
randomized trial evaluating the e ects of sunscreen and the
antioxidant beta carotene over a 4-year period found that those
using topical sunscreen had a 40% reduction in SCCs but no
decrease in BCCs.46
The frequency and intensity of sun exposure may also be
important. Solar exposure in intermittent, intense increments
increases the risk of BCC more than a similar dose delivered
more continuously over the same period of time.47 Evidence in
renal transplant recipients provides additional support to the
concept that acute or intermittent sun exposure increases the
risk of BCC.48 Additionally, indirect support for an important
role for sun exposure is derived from a large, nested case–con-
trol study of female nurses.49 In the study, a contributory role of
extensive sun exposure was suggested by the finding that
women in the highest quartile for baseline serum vitamin D lev-
els were at greater risk for the subsequent development of BCC
than women in the lowest quartile (odds ratio [OR] 2.07; 95%
confidence interval [CI]: 1.52–2.80). The authors proposed that
the plasma vitamin D level was a potential indicator of the
degree of long-term sun exposure.
3.2.2 Tanning Beds
The use of tanning beds may increase the risk for early develop-
ment of BCC.50,51,52,53,54 A cohort study of approximately 73,000
female nurses found that women who used tanning beds more
than six times per year during high school or college were more
likely to develop BCC than women who did not use tanning
booths during these time periods (adjusted hazard ratio 1.73;
95% CI: 1.52–1.98).55 A contribution of UV light exposure from
indoor tanning to BCC is also suggested by the results of a 2012
meta-analysis of observational studies.53 Subjects with a history
of any tanning bed use were more likely to develop BCC than
those who had never used tanning beds (relative risk 1.29; 95%
CI: 1.08–1.53). The relative risk for BCC for individuals who
began tanning prior to age 25 was 1.40 (95% CI: 1.29–1.52). A
subsequent population-based case–control study, including
approximately 650 cases of BCC and 450 controls, found that
tanning bed users had a 60% increased risk of developing a BCC
at or before the age of 50 years (OR 1.6; 95% CI: 1.3–2.1).54 The
risk was doubled for those reporting a first use of tanning devi-
ces before the age of 20.
3.2.3 Chronic Arsenic Exposure
Superficial multicentric BCC occurs 30 to 40 years after chronic
exposure of arsenic, which may occur as a result of ingesting
contaminated drinking water, seafood, or medications.56,57,58,59
3.2.4 Ionizing Radiation
Superficial therapeutic ionizing radiation, as for facial acne,
psoriasis, or tinea capitis, increases the risk of NMSC, including
BCC.60,61 The latency period for development of BCCs is esti-
mated to be approximately 20 years, and lesions are limited to
sites with radiation exposure. Due to the advent of other
Treatment of Squamous and Basal Cell Carcinoma of the Skin
44

e ective therapies, the use of ionizing radiation for the treat-
ment of inflammatory skin conditions has declined.
Ionizing radiation used to treat childhood cancers also
increases the risk for the subsequent development of BCC. This
was illustrated in a study of 776 subjects documenting an
approximately 10-fold higher rate of BCC than was expected in
this population.62 All of the BCCs were located within the radia-
tion field. In addition, a case–control study of 199 patients with
a history of both childhood cancer and BCC and 597 controls
with a history of childhood cancer without BCC found a linear
dose–response relationship between the radiation dose and risk
for BCC. An increase in risk was detected among patients who
received at least 1 Gy of radiation to the skin, and patients who
received 35 Gy or more were 40 times more likely to develop
BCC than those who were not treated with radiation (OR 39.8;
95% CI: 8.6–185). The treatment of other noncutaneous disor-
ders with radiation therapy (RT) has also been associated with
the appearance of BCC.60,63,64
Studies of survivors of the atomic bomb explosions in Japan
support the role of exposure to ionizing radiation in the devel-
opment of BCC. In a retrospective study of bomb survivors, the
incidence of subsequent BCC increased with proximity to the
hypocenter of the explosion.65
3.2.5 Therapeutic Exposure
Therapeutic exposure to PUVA for cutaneous disorders such as
psoriasis increases the risk of NMSC, particularly SCC.66,67 The
risk of BCC in patients treated with PUVA is lower than the risk
for cutaneous SCC. In a 30-year prospective cohort study docu-
menting the incidence of NMSC in patients given PUVA for
psoriasis, the increase in risk for BCC was modest compared
with cutaneous SCC.68
3.2.6 Photosensitizing Drugs
The association of BCC with UV light exposure has led to
questions about the impact of photosensitizing drugs on devel-
opment of BCC. An association between prior use of photosensi-
tizing tetracyclines or diuretics and increased risk for BCC has
been documented in several observational studies.69,70 In addi-
tion, an American population-based case–control study of
1,567 adults with BCC and 1,906 controls found a minor
increase in risk for multiple BCC (OR 1.4; 95% CI: 1–2.1) and
BCC before the age of 51 (OR 1.5; 95% CI: 1.1–2.1) among partic-
ipants who recalled use of a photosensitizing medication.69
Additional studies are necessary to clarify the relationship
between photosensitizing drugs and BCC.
3.2.7 Immunosuppression
Chronic immunosuppression (as occurs with solid organ trans-
plantation and with human immunodeficiency virus [HIV]
infection) may increase risk for the development of BCC,
although the increase in risk is less than that observed for
SCC.71 The risk for BCC after solid organ transplantation appears
to increase linearly over time, whereas the risk for SCC rises
exponentially.72,73 The increased risk for skin cancer in organ
transplant recipients is attributed to chronic exposure to im-
munosuppressive agents. The specific impact of systemic
glucocorticoid therapy on BCC risk is uncertain; studies per-
formed in patients without a history of organ transplantation
conflict on whether systemic glucocorticoid therapy signifi-
cantly increases risk for BCC.73,74,75
Support for an increased risk for BCC among HIV-positive
individuals was demonstrated in a retrospective cohort study of
HIV-positive (n =6,560) and HIV-negative (n =36,821) non-His-
panic white patients. The study found that patients with HIV
infection were approximately twice as likely to develop BCC
than patients without HIV infection (adjusted rate ratio 2.1;
95% CI: 1.8–2.3).76,77
3.2.8 Previous Personal History of
Nonmelanoma Skin Cancer
A personal history of BCC or SCC is strongly associated with
subsequent BCC or SCC.15
There is an approximate 20%
increased risk of a subsequent lesion within the first year after a
skin cancer has been diagnosed.15,78,79 The mean age of occur-
rence for these NMSCs is the mid-60 s.14,15 In addition, several
studies have found that individuals with a history of skin cancer
have an increased risk of a subsequent diagnosis of a noncuta-
neous cancer.80,81,82,83,84 In the absence of other risk factors or
evidence of a defined cancer susceptibility syndrome, as dis-
cussed below, skin cancer patients are encouraged to follow
screening recommendations for the general population for sites
other than the skin.
Genetic variation may play a role in susceptibility to BCC.
Some gene sequence variants that are a liated with
increased risk of BCC also correlate with light skin pigm enta-
tion.85 In addition, genome-w ide association studies have
identified genetic variants (see below) that m ay influence
BCC risk through other pathways, such as an e ect on the
growth or di erentiation of basal layers of the epidermis or
an e ect on the P53 tum or suppressor gene or hedgehog
pathways.86,87,88,89,90,91,92
Genes that a ect the immune response may also impact sus-
ceptibility to BCC. Cytotoxic lymphocyte-associated antigen-4
(CTLA-4) is expressed on regulatory T cells and is involved in
UV-induced immune tolerance. In a case–control study, genetic
variation at the CTLA-4 locus influenced the risk of BCC, partic-
ularly among patients with a higher number of severe
sunburns.93
The most significant genetic components for BCC are the
PTCH1 and PTCH2 genes. PTCH1 mutations in the gene coding
for the transmembrane receptor protein PTCH1, or PTCH, are
associated with basal cell nevus syndrome (BCNS) and sporadic
cutaneous BCCs. PTCH1, the human homolog of the Drosophila
segment polarity gene patched (ptc), is an integral component
of the hedgehog signaling pathway, which serves many devel-
opmental (appendage development, embryonic segmentation,
neural tube di erentiation) and regulatory (maintenance of
stem cells) roles.94,95
In the resting state, the transmembrane receptor protein
PTCH1 acts catalytically to suppress the seven-transmembrane
protein Smoothened (SMO), preventing further downstream
signal transduction.96,97 Stoichiometric binding of the hedgehog
ligand to PTCH1 releases inhibition of SMO, with resultant acti-
vation of transcription factors (GLI1, GLI2), cell proliferation
Treatment of Squamous and Basal Cell Carcinoma of the Skin
45

genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.97,
98 Thus, the balance of PTCH1 (inhibition) and SMO (activation)
manages the essential regulatory downstream hedgehog signal
transduction pathway. Loss-of-function mutations of PTCH1 or
gain-of-function mutations of SMO tip this balance toward
constitutive activation, a key event in potential neoplastic
transformation.
Demonstration of allelic loss on chromosome 9q22 in both
sporadic and familial BCCs suggested the potential presence of
an associated tumor suppressor gene.99,100 Further investigation
identified a mutation in PTCH1 that localized to the area of
allelic loss.101 Up to 30% of sporadic BCCs demonstrate PTCH1
mutations.102 In addition to BCC, medulloblastoma and rhabdo-
myosarcoma, along with other tumors, have been associated
with PTCH1 mutations. All three malignancies are associated
with BCNS, and most people with clinical features of BCNS
demonstrate PTCH1 mutations, predominantly truncation in
type.103
Truncating mutations in PTCH2, a homolog of PTCH1 mapping
to chromosome 1p32.1–32.3, have been demonstrated in both
BCC and medulloblastoma.104,105 PTCH2 displays 57% homology
to PTCH1, di ering in the conformation of the hydrophilic
region between transmembrane portions 6 and 7, and the
absence of C-terminal extension.106 While the exact role of
PTCH2 remains unclear, there is evidence to support its involve-
ment in the hedgehog signaling pathway.104
3.2.9 Nevus Sebaceous
Nevus sebaceous (Fig. 3.1, Fig. 3.2, Fig. 3.3) is an uncom-
mon congenital hamartoma of the skin composed of epidermal,
follicular, sebaceous, and apocrine elements. BCC may develop
within nevus sebaceous, though this occurrence is rare. BCCs
are the most commonly reported malignant neoplasm occur-
ring in roughly 0.5 to 7% of sebaceous nevi.107,108 In a retrospec-
tive study of 596 nevus sebaceous excisions from adults and
Fig. 3.1 Nevus sebaceous (NS). In infancy and childhood, NS remains
mostly unchanged, due to the quiescence of sebaceous glands. At
puberty, under hormonal influences, lesions thicken and become
verrucous or nodular. Rapid, circumscribed enlargement or ulceration
should arouse suspicion for malignant transformation.
Fig. 3.2 Nevus sebaceous (NS). The diagnosis of NS is usually based
upon the clinical presentation. In most cases, NS is apparent at birth
and presents as a well-defined, thin, yellow-orange or tan, oval, round,
or linear plaque. Sometimes lesions are not noticed until later in
childhood or after puberty. A biopsy for histopathologic confirmation
may be warranted if the diagnosis is uncertain. The definitive
treatment of NS is full-thickness excision. The decision to excise should
be made in individual patients, based upon age, extension, and
location of the lesion, and patient’s or parents’ concern about the
cosmetic appearance and/or risk of malignancy.
Fig. 3.3 Nevus sebaceous (NS). A variety of benign and malignant
epithelial neoplasms may arise within NS. Benign tumors include
trichoblastoma, syringocystadenoma papilliferum, trichilemmoma,
sebaceoma, nodular hidradenoma, hidrocystoma, and eccrine poroma.
Malignant neoplasms include basal cell carcinoma, apocrine carcino-
ma, trichilemmal carcinoma, sebaceous carcinoma, microcystic ad-
nexal carcinoma, porocarcinoma, and squamous cell carcinoma. The
exact incidence and the lifetime risk of malignancy arising in NS are
unknown. The risk of malignancy increases with age, but basal cell
carcinomas have been reported also in children.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
46

children, BCC was detected in specimens from five adults
(0.8%).109 A separate review of 631 children with 651 lesions of
nevus sebaceous found that BCC may also develop within nevus
sebaceous in children; BCC was found in excisional specimens
from five patients (0.8%).107
3.2.10 Inherited Disorders
While most arise sporadically, BCC is also associated with sev-
eral clinical syndromes including Bazex syndrome, Gorlin’s syn-
drome (BCNS), and highly UV-sensitive conditions such as
xeroderma pigmentosum (XP). Constitutive activation of the
sonic hedgehog signaling pathway is thought to play a signifi-
cant role in the majority of BCC pathogenesis.110,111 Bazex syn-
drome is characterized by multiple BCCs and follicular
atrophoderma.112 Rombo syndrom e presents with atropho-
derma vermiculatum and vellus hair cysts with milia-like
appearance.113 Patients with XP are at increased risk for BCC as
well as SSCs and melanomas. The incidence of these malignan-
cies for individuals with XP under the age of 20 is approxi-
mately 2,000 times that seen in the general population.114,115,116
3.2.11 Family History
Individuals with BCCs and/or SCCs report a higher frequency of
these cancers in their family members than do controls. The
importance of this finding is unclear. Apart from defined
genetic disorders with an increased risk of BCC, a positive fam-
ily history of any skin cancer is a strong predictor of the devel-
opment of BCC.
3.2.12 Nevoid BCC Syndrome (Gorlin’s
Syndrome)
Nevoid BCC syndrome is also known as the Gorlin–Goltz syn-
drome and is inherited in an autosomal dominant manner;
however, approximately 30–50% of cases represent sporadic
mutations.117,118,119
Its prevalence has been estimated at
approximately 1 in 56,000 and manifests in young adulthood.120
In most cases, the abnormality is due to a mutation in the
patched gene (PTCH) of chromosome 9 q22–q31, thereby
resulting in upregulated proliferation.119,121,122
Currently, no genetic test has been developed for widespread
use, and diagnosis remains based on clinical criteria. The diag-
nosis may be established with documentation of two major cri-
teria or one major and two minor criteria123,124 (Table 3.1).
3.3 Clinical Features
The clinical features of nevoid BCC syndrome include the pres-
ence of numerous BCCs with a higher prevalence of nodular,
superficial, and infundibulocystic types (Fig. 3.4). Patients
may also have cysts of the skin (steatocystomas) and bone, par-
ticularly the mandible ( Fig. 3.5) and maxilla (odontogenic
keratocysts).118,123 Also present are skeletal anomalies including
spinal and rib deformities, excessive ossification of cranial
bones and falx cerebri with concurrent frontal bossing and
bridging of the sella turcica.118,123,125
Palmoplantar pits
(Fig. 3.6 and Fig. 3.7) may appear during the second decade
of life in addition to psychiatric or neurologic dysfunction
including schizophrenia, mental retardation, and cerebellar
degeneration.126,127 In the absence of distinct criteria, clinical
suspicion of Gorlin’s syndrome may be indicated for any patient
with multiple histologically proven BCCs arising at a young age.
Morbidity and premature mortality in nevoid basal cell carci-
noma syndrom e (NBCCS) are primarily related to the develop-
ment of skin cancers and other tumors associated with the
syndrome.
The BCNS (NBCCS Gorlin’s syndrome) is a rare, autosomal
dominant disorder due to germline mutations of the human
patched gene (PTCH). The histologic appearance of the BCCs in
BCNS does not di er from those seen in sporadic cases. The
Fig. 3.4 Gorlin’s syndrome. People with Gorlin’s syndrome need
education about the syndrome, and may need counseling and support
because coping with the multiple BCCs and multiple surgeries is often
difficult. Genetic counseling is advised for prospective parents, since
one parent with Gorlin’s syndrome have 50% chance that their child
will also be affected.
Table 3.1 Major and minor diagnostic criteria for diagnosis of nevoid
basal cell carcinoma syndrome (NBCCS)
Major criteria

Minor criteria
Multiple (>2) BCCs at any age or
one BCC less than 20 y or >10 BCCs
Congenital skeletal defects: bifid,
fused, splayed, or missing rib, or
bifid, wedged, or used vertebra
Histologically proven odontogenic
keratocyst or a polyostotic bone
cyst
Cardiac or ovarian fibroma
Palmar or plantar pits (3 or more) Medulloblastoma
Ectopic calcification: bilamellar or
early (<20 y) calcification of the
falx cerebri
Large head with occipitofrontal
circumference >97th percentile,
with frontal bossing
Family history of basal cell nevus
syndrome
Congenital malformation: cleft lip
and/or palate, polydactyly, con-
genital eye defect such as cataract,
microphthalmos or coloboma
Treatment of Squamous and Basal Cell Carcinoma of the Skin
47

diagnosis should be suspected in patients who present with
multiple BCCs, especially when these occur at an early age and
are located on the trunk. These patients require aggressive
approaches to therapy and frequently are disfigured from surgi-
cal treatments by the third decade of life. A ected patients have
distinct clinical features and predilection for multiple tumors,
especially multiple BCCs, usually by age 35.99 Clinical features
often include macrocephaly, hypertelorism, bifid ribs, palmar
and plantar pitting, osseous cysts (of the mandible), and medul-
loblastoma (3–5%).99,128
3.4 Prevention of Basal Cell
Carcinoma
The primary approach to the prevention of BCCs is protection
from UV radiation exposure. The various techniques to mini-
mize solar exposure are discussed elsewhere. Data on the pre-
vention of BCC through additional drugs or therapies are
controversial.129,130,131,132 The results of an 11-month random-
ized trial of 240 patients with actinically damaged skin sug-
gested that celecoxib may be beneficial for chemoprevention. In
this trial, patients treated with celecoxib (200 mg twice daily
for 9 months) developed fewer BCCs than patients who were
given placebo (adjusted rate ratio 0.40; 95% CI: 0.18–0.93).133 In
contrast, a Danish population-based case–control study failed
to find an association between the use of celecoxib or other pre-
scription nonsteroidal anti-inflammatory drugs (NSAIDs) and
overall risk for BCC.134 Another population-based case–control
study did not find an association between the use of any
NSAIDs and the overall risk of BCC.135 In subgroup analyses, a
Fig. 3.5 Mandibular cysts of Gorlin’s syndrome. When patients with
Gorlin’s syndrome have mandible tumors, they are characterized as
keratocystic odontogenic tumors. Above is a Panorex example.
Fig. 3.6 Palmar pits of Gorlin’s syndrome. Palmar and plantar pits
appear as punctiform depressions in the skin of palms and soles of feet.
These changes are caused by a partial or complete absence of the
stratum corneum. They are usually asymmetric, flesh-, pink- or red-
colored, and range from 2 to 3 mm in diameter and 1 to 3 mm in
depth. In Gorlin’s syndrome, pits appear in 30 to 65% of patients by the
age of 10 years and in 85% of patients over the age of 20 years.
Fig. 3.7 Plantar pits of Gorlin’s syndrome.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
48

modest risk reduction was observed among long-term users of
ibuprofen ( OR 0.85; 95% CI: 0.77–0.94), and risk was further
reduced among mono-users (OR 0.61; 95% CI: 0.48–0.78).135
The Australian Oral Nicotinamide to Reduce Actinic Cancer
(ONTRAC) trial preliminarily showed that nicotinamide, a form
of vitamin B3, significantly reduced the rates of new cutaneous
malignancies in people at high risk of the disease.136 Taken as a
twice-daily pill, nicotinamide reduced the incidence of new
nonmelanoma skin cancers (NMSCs) by 23%. AK was reduced in
the nicotinamide group by 11% at 3 months and by 20% at 9
months of usage. Researchers believe that nicotinamide thus
helps replenish cellular energy after sunlight exposure, giving
cells the energy boost they need to repair deoxyribonucleic acid
(DNA) damage and prevent immune suppression.136
3.5 Clinical Presentation
Approximately 70% of BCCs occur on the face, consistent with
the etiologic role of solar radiation. Fifteen percent present on
the trunk, and only rarely is BCC diagnosed on areas like the
penis, vulva, or perianal skin. Clinically, BCCs appear as pearly
and telangiectatic papules or nodules with or without ulcera-
tion, or as indurated, erythematous, or ulcerated patches with a
discrete papular border, and may be pigmented. BCCs display
di erent morphological growth patterns: superficial or multifo-
cal, nodular, micronodular, infiltrating, sclerosing (sclerodermi-
form), or morpheaform.
The diversity in the phenotypic appearance of BCCs indicates
that the cell of origin may be a stem or progenitor cell. More-
over, these observations raise the question as to whether BCC is
a monoclonal tumor or whether it is the result of field cancer-
ization. Studies investigating clonal patterns of X chromosome
inactivation suggest that the majority of BCCs do represent
monoclonal tumors and that anatomically distinct BCCs may
sometimes share the same cellular origin.137
About 30% of BCCs are superficial BCCs. For unclear reasons,
men have a higher incidence of superficial BCC, in particular,
than women. Superficial BCCs most commonly occur on the
trunk, and typically present as slightly scaly, nonfirm macules,
patches, or thin plaques light red to pink in color (Fig. 3.8 and
Fig. 3.9). The center of the lesion sometimes exhibits an atro-
phic appearance and the periphery may be rimmed with fine
translucent papules. A shiny quality may be evident when a
superficial BCC is illuminated. Occasionally, spotty brown or
black pigment as shown in Fig. 3.10 is present, which may
contribute to confusion with melanoma.138 These lesions are
referred to as pigmented BCCs. However, both nodular and
superficial BCCs can produce pigment. Superficial BCCs tend to
grow slowly, and can vary in size from macules measuring just
a few millimeters in diameter to lesions several centimeters in
diameter or more if left untreated. Superficial BCCs are usually
asymptomatic.138,139,140
Nodular BCCs, which represent about 60% of cases, typically
present on the face as a pink or flesh-colored papule. As shown
in Fig. 3.11, Fig. 3.12, Fig. 3.13, Fig. 3.14, these lesions
usually have a pearly or translucent quality and a telangiectatic
vessel is frequently seen within the papule. Ulceration is fre-
quent, and the term “rodent ulcer” refers to these ulcerated
nodular BCCs. Nodular BCCs in particular may resemble adnexal
Fig. 3.8 Superficial basal cell carcinoma (BCC). Superficial BCCs are
usually asymptomatic. They present as a flaky erythematous lesions
with irregular borders that are slightly elevated.
Fig. 3.9 Superficial basal cell carcinoma (BCC). These often grow slowly
but can grow to several centimeters in size if neglected.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
49

tumors or, in some regions, SCC, as these BCCs demonstrate a
variety of types of di erentiation including basosquamous or
metatypical, cystic, adenoid, pigmented, and infundibulocystic
di erentiation.141,142
Micronodular BCC manifests a plaque-like indurated lesion
with a poorly demarcated contour ( Fig. 3.15).143,144 Lesions
invade deeply in the dermis and so have an increased incidence
of recurrence.145,146,147
Micronodular BCC manifests tumor
nests with roughly the same shape and contour as nodular BCC,
but which are nonetheless smaller and widely dispersed in an
often asymmetric distribution extending deeper into the der-
mis and/or subcutis, as shown in Fig. 3.16.
Morpheaform (sclerodermiform) or sclerosing BCCs consti-
tute 5 to 10% of BCCs. These lesions are typically smooth, flesh-
colored, or very lightly erythematous papules or plaques that
are frequently atrophic resembling scleroderma or “scar-like”;
they usually have a firm or indurated quality with ill-defined
borders. Some authors group morpheaform, infiltrative, and
micronodular as “aggressive-grow th” BCC, because they behave
similarly.22 Infiltrative and micronodular subtypes are less
Fig. 3.10 Pigmented superficial basal cell carcinoma (BCC). It may also
be pigmented or resembling a benign inflammatory process, especially
psoriasis, seborrheic eczema, or nummular dermatitis.
Fig. 3.11 Nodular basal cell carcinoma (BCC). The nodular type of basal
BCC presents as a pink papule often with pearly borders and fine
telangiectasias.
Fig. 3.12 Nodular basal cell carcinoma (BCC).
Fig. 3.13 Ulcerated nodular basal cell carcinoma (BCC). BCC grows
over time. With increase in size, it can ulcerate.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
50

common than the morpheaform BCC (Fig. 3.17, Fig. 3.18,
Fig. 3.19).
Several other BCC subtypes have been described and have a
mixed histology and features of more than one histologic sub-
type (Fig. 3.20 and Fig. 3.21). BCCs may show a variety of
specific cell lineage di erentiation features that do not impact
prognosis. These include, but are not restricted, to keratotic
BCC, infundibulocystic BCC, follicular BCC, which shows colli-
sion features with pilomatricoma, pleomorphic BCC, BCC with
eccrine di erentiation, BCC with sebaceous di erentiation, the
fibroepithelioma of Pinkus, and the BCC with myoepithelial dif-
ferentiation. Basosquamous cell carcinoma is an additional sub-
type often noted to have a potential for invasion similar to SCC.
Clinicians familiar with the clinical manifestations of BCC are
often able to make the diagnosis based upon clinical examina-
tion. Dermoscopy, shown in Fig. 3.22 and Fig. 3.23, is also
an important diagnostic tool that every physician who works
with skin cancer should be familiar with. Although biopsies are
required for a definitive diagnosis, dermoscopy may be used to
aid in the clinical evaluation of lesions that are suspicious for
BCC.148,149 Common dermatoscopic features of BCC include
“arborizing” blood vessels (discrete, thickened, red blood
vessels that branch like a tree) and blue-gray ovoid nests. Pig-
mented BCCs often demonstrate brown leaf-like structures on
dermatoscopic examination, which represent heavily pig-
mented aggregates of tumor cells.149
A skin biopsy is usually performed to provide histologic con-
firmation of the diagnosis. In cases for which the clinical diag-
nosis of BCC appears certain and the tumor lacks clinical
features associated with a high risk for tumor recurrence, clini-
cians experienced in the diagnosis of BCC sometimes choose to
perform the definitive treatment without previous biopsy.
However, the decision not to perform a biopsy prior to defini-
tive treatment is not without risk. Because the histologic fea-
tures of a tumor provide additional information on the risk for
tumor recurrence following treatment, not performing a biopsy
prior to definitive treatment may result in a failure to detect a
tumor with aggressive histologic features that might be best
managed with a di erent approach to therapy. The misdiagno-
sis of a di erent tumor as BCC (amelanotic melanoma, Merkel
cell carcinoma) is an additional risk of deferring a biopsy,
mostly for those who use destruction methods like curettage
and electrodesiccation instead of excision biopsy. To reduce the
risk for patient mismanagement, one should always perform a
Fig. 3.14 Pigmented nodular basal cell carcinoma (BCC). BCC may also
be pigmented, and sometimes it is easy to confuse it with a malignant
melanoma. Pigment may be present in different concentrations in
pigmented BCC.
Fig. 3.15 Micronodular basal cell carcinoma (BCC). Micronodular BCCs
present as multiple small aggregated nodules. These can invade
deeper into the skin and be more aggressive.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
51

biopsy when the diagnosis is uncertain or the lesion exhibits
features atypical for BCC, the patient lacks a prior history of
BCC, or the lesion exhibits clinical features suggestive of a BCC
with a high risk for recurrence.
Shave biopsies, punch biopsies, and excisional biopsies may
all be used for the initial tissue sampling for diagnosis of BCC.
Although shave and punch biopsies are frequently performed
for diagnosis due to the simplicity of these procedures, clini-
cians should be aware that biopsies that remove only a portion
of the lesion do not provide an accurate assessment of the his-
tologic subtype of a tumor.150,151,152,153 With punch biopsies, an
aggressive histologic subtype may be missed in nearly 20% of
cases.150,151 A retrospective study in which the majority of
biopsy procedures were shave biopsies (230 shave biopsies and
Fig. 3.16 Micronodular basal cell carcinoma (BCC) histopathology.
Characteristic feature of small cell nests scattered through the tissue
without surrounding stroma.
Fig. 3.17 Morpheaform basal cell carcinomas (BCCs) are typically
smooth, flesh- or ivory-colored, or very lightly erythematous papules or
plaques that are frequently atrophic and sometimes with telangiectasias.
Fig. 3.18 Morpheaform basal cell carcinoma. They usually are firm or
indurated with ill-defined borders and may resemble scleroderma.
Fig. 3.19 Morpheaform basal cell carcinoma.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
52

27 punch biopsies) found that an aggressive histologic subtype
was missed in 7% of cases.152
The di erential diagnosis varies w ith the pathologic sub-
type of BCC with nodular, superficial, or m orpheaform hav-
ing various presentations. Early nodular variants with little
ulceration clinically m ay be identical to benign growths such
as derm al nevi, sm all epidermal inclusion cysts, or even
sebaceous hyperplasia. A single lesion of m olluscum conta-
giosum has a sim ilar appearance, as does am elanotic m ela-
noma. Larger lesions with central ulceration can appear cup
shaped. These can resemble SCC, keratoacanthom as. Superfi-
cial BCCs may be confused with inflam matory disorders of
the skin such as nummular eczem a or psoriasis; therefore,
superficial BCC should be considered when a lesion pre-
sum ed to be inflam m atory fails to respond to topical corti-
costeroids. Morpheaform BCCs frequently appear in or
adjacent to a scar or other site of trauma. The induration of
the lesion simulates localized scleroderm a. Additionally, pig-
m ented nodular or superficial BCCs m ay resem ble melanom a
or, less likely, a benign nevus.
Fig. 3.20 (a) Adenoid cystic basal cell carcinoma (BCC). Raised nodule with a thin rim of skin at the periphery. It showed a central ulcer with crusting
and irregular rolled borders. (b) BCC with adenoid differentiation of the nose requiring surgical excision.
Fig. 3.21 Histopathology adenoid cystic basal cell
carcinoma. Histological picture showing a pre-
dominant adenoid pattern with thin strands of
basaloid cells in a reticulate arrangement, with
many tubules and cystically dilated spaces con-
taining mucin.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
53

3.6 Biopsy Techniques
Multiple biopsy techniques exist and should be implemented
judiciously to each individual patient circumstance. The tech-
nique should ideally produce the information necessary for
diagnosis and possible staging while maintaining subsequent
options for follow-up procedures and long-term care. Disregard
to potential follow-up procedures could hinder successful
excision, adequate margins, or cosmesis. For example, failure to
properly orient the long axis of an incisional or excisional
biopsy with respect to future resection could complicate the
eventual closure and limit reconstructive options.154
3.6.1 Incisional Biopsy
The incisional biopsy is typically indicated in large lesions in
which excision would cause a large defect area, unable to be
managed with primary closure. It may also be used in cosmeti-
cally sensitive areas before final pathologic diagnosis can be
obtained, and a plan for definitive closure/reconstruction can
be obtained. The clinician should also attempt to excise a small
margin of tissue with the specimen to aid the pathologist in
comparing the normal to the abnormal tissue.
3.6.2 Excisional Biopsy
This is the preferred method in relatively small lesions where
primary closure and a good cosmetic outcome can be achieved.
The advantages of excisional biopsy also include the ability to
provide the pathologist with the native architecture, orienta-
tion, depth, and appearance of surrounding tissues. In general,
margins of 1 to 2 mm are usually su cient for the primary exci-
sion and initial diagnosis, with special attention to excise below
the base of the lesion to determine potential Breslow thickness.
Furthermore, postoperative margin assessment (POMA) may be
requested to ensure adequate excision or diagnose a positive
margin that may be missed with traditional pathology
sections.155
3.6.3 Punch Biopsy
This is a relatively simple m ethod of obtaining a sample of
tissue from a cutaneous lesion. Multiple punches and propri-
ety devices are available including the Tru-Cut needle to
obtain a core of tissue from an unknown m ass in the skin
and/or subcutaneous tissues. The diameter of the punch m ay
be determined by the provider to ensure adequate tissue is
sent for pathology.
3.6.4 Shave Biopsy
Shave biopsy is the most common technique used by dermatol-
ogists and primary care physicians. The defect site is usually
managed by allowing it to heal via secondary intention with ad-
equate scar outcomes. While advantageous in regard to ease of
use, cost, and minimal complications, this technique may fail to
determine the depth of the tumor margin, and thereby prevent-
ing proper staging of the lesion.
3.6.5 Fine-Needle Aspiration Biopsy
This is usually reserved for metastatic lesions that may be easily
seen or palpated in the skin or subcutaneous tissue. It is per-
formed by making multiple passes with a hollow-bore needle
into the lesion while applying suction on the syringe. The har-
vested tissue is then placed directly onto a slide for further fixa-
tion and analysis.156
3.7 Approach to Treatment
3.7.1 Topical Therapies
Topical therapies include 5-fluorouracil (5-FU) and imiquimod
and must be applied for several weeks to maximize potential
benefit. In general, both induce mild to moderate inflammatory
reactions at the sites of application.157
Fig. 3.22 Dermoscopy of pigmented basal cell carcinoma showing blue
ovoid nests, structureless areas, and ulceration.
Fig. 3.23 Dermoscopy basal cell carcinoma showing typical absence of
pigment network with pinkish color, asymmetrical arborizing vessels,
milia formation, and leaflike areas on the periphery of the lesion.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
54

Topical 5-Fluorouracil
5-FU exerts its a ects through interference of DNA synthesis by
inhibiting thymidylate synthase, therefore rapidly proliferating
cells are most sensitive to its cytotoxic e ect. Topical 5-FU is
available in a variety of strengths and formulations; the 5%
cream or solution is used for the treatment of BCC applied twice
daily for at least 3 to 6 weeks; however, treatment may con-
tinue until reaching the desired clinical response.157
Treatment with topical 5-FU should be restricted to superfi-
cial BCCs in noncritical locations.157 Various relatively small
studies have documented cure rates of up to 95% using 5-FU
cream in patients with carefully selected superficial BCCs,
although lower cure rates are reported by others.157,158 Treat-
ment of nonsuperficial, recurrent, or other high-risk BCCs with
5-FU results in low cure rates and is generally inadvisable.159,160,
161 In particular, nodular and aggressive BCCs are generally con-
sidered contraindications to topical 5-FU given that superficial
treatment may give the false impression of a cure despite per-
sistent dermal disease.
Topical 5-FU causes a brisk inflammatory reaction in the
treated sites, which is an indication of activity. Prior to treat-
ment, patients should be thoroughly educated on anticipated
side e ects, including undesired cosmetic e ects, pain, ery-
thema, edema, erosions, and ulceration with potential drainage.
Therapy may be discontinued if the inflammation is not toler-
ated. Alternatively, tolerance may be improved through reduc-
tion of drug concentration, application of an emollient or
application of an intermediate-potency topical steroid.159,160,161
Special care should be taken when applying 5-FU to areas near
the eyes, lips, and nose as well as avoiding intense sun exposure
during treatment.
Following discontinuation of topical 5-FU therapy, healing
generally takes place over the ensuing 2 weeks or more. The
residual erythema and occasional hyperpigmentation usually
fade with time. In general, long-term favorable cosmetic results
are obtained with observation. Other unusual side e ects
include persistent telangiectasias, pigmentary changes, and
hypertrophic scarring in high-risk areas.
3.7.2 Imiquimod
Imiquimod 5% cream is an immune response modifier (Toll-like
receptor 7 agonist) approved for treatment of superficial BCCs
in low-risk sites. Imiquimod is thought to promote apoptosis in
skin cancer cells by circumventing the antiapoptotic mecha-
nisms deployed by tumor cells or by stimulating monocytes/
macrophages and dendritic cells to produce cytokines that
stimulate cell-mediated immunity.162,163,164
The e cacy of imiquimod for superficial BCC has been
documented in m ulticenter randomized trials that compared
imiquim od 5% cream (applied once daily five or seven tim es
per week for 6 weeks) in a total of 724 patients with super-
ficial BCC.164 Twelve weeks after treatment, the histologic
clearance rates for the 5- and 7-day im iquim od treatment
groups were 82 and 79%, respectively, compared with 3% in
the control group. The severity of erythema, erosion, and
scabbing/crusting was associated w ith higher clearance
rates; however, long-term follow-up was not reported. This
was corroborated in a random ized trial that assessed the
response of superficial BCC to 6 weeks of daily therapy with
im iquim od 5% cream .165 Twelve weeks after treatm ent, his-
tologic clearance rates in the im iquim od and vehicle groups
were 80 and 6%, respectively.165
Although imiquimod’s e cacy has been established, clini-
cians should be aware that the likelihood of treatment success
is higher with surgical excision (SE). A trial of 257 patients with
superficial BCC and 244 patients with nodular BCC were ran-
domly assigned to treatment with imiquimod 5% cream (once
daily for 6 weeks for superficial BCC and once daily for 12 weeks
for nodular BCC) or SE with a 4-mm margin found that patients
treated with SE were significantly less likely to experience
treatment failure or tumor recurrence within 3 years.166 Among
the patients with superficial BCC, clinical cure rates from SE and
imiquimod were 98 and 85%, respectively.166 Patient satisfac-
tion with the cosmetic appearance of sites of imiquimod treat-
ment and SE was also similar at 6 months and 3 years after
treatment.166
The thickness of a superficial BCC may influence the likeli-
hood of response to imiquimod therapy. A retrospective study
of 127 biopsy specimens from superficial BCCs that were subse-
quently treated with imiquimod (applied 5 days per week for
6 weeks) found that while 11 of 19 tumors (58%) >0.4 mm deep
recurred after treatment, none of 108 tumors ≤0.4 mm deep
recurred (mean follow-up 34 months, range 3–91 months).167 If
these findings are supported by future investigations, the depth
of superficial BCC may become a consideration in the selection
of imiquimod treatment.
The few randomized trials that have evaluated the use of imi-
quimod as an adjunctive therapy for nodular BCC prior to SE
have yielded conflicting findings.168,169 In a randomized trial of
70 patients with nodular BCC on the face, 4 weeks of imiquimod
treatment prior to Mohs surgery was associated with reduc-
tions in tumor size and surgical defect size. However, a smaller
randomized trial failed to find a statistically significant benefit
of imiquimod therapy.168 There is also a theoretical concern
that pretreatment with imiquimod could contribute to false
negative surgical margins by inducing noncontiguous areas of
residual tumor.170
In general, imiquimod is used for the treatment of primary
superficial BCCs in low-risk sites where recurrence is unlikely
to be accompanied by substantial morbidity. Because of concern
for consistent patient adherence to the longer treatment period
suggested for nodular BCC and the availability of more e ective
treatment,166 imiquimod is not routinely used for the treatment
of nodular BCC. Imiquimod is reserved for the treatment of
nonsuperficial BCCs only in those patients who are poor surgi-
cal candidates or who have limited life expectancies. The selec-
tion of imiquimod over a surgical procedure for superficial BCC
usually stems from patient-specific factors such as patient pref-
erence to avoid surgery.166
The standard regim en for im iquim od treatm ent of superfi-
cial BCC is application of imiquimod to the BCC once daily
5 days per week for 6 weeks. If the irritation becom es too
severe, the patient m ay take 2 to 3 days o and then resum e
treatment. Local skin irritation is an expected side e ect of
imiquim od therapy. Patients may experience itching, weep-
ing, redness, soreness, bleeding, and/or pain within the
treated area.166 In addition, hypopigm entation m ay develop
after therapy.166,171
Treatment of Squamous and Basal Cell Carcinoma of the Skin
55

3.8 Photodynamic Therapy
Photodynamic therapy (PDT) utilizes both light and porphyrins
to cause tumor destruction. PDT is applied to the lesion, which
results in a higher concentration of the porphyrins within the
cancerous cells, and the ability to focus light on the involved
area. Although PDT has been approved for the treatment of BCC
in many European countries, U.S. Food and Drug Administration
(FDA) approval has not been granted for the treatment of BCC.
To perform PDT, a photosensitizing porphyrin such as 5-ami-
nolevulinic acid (ALA) or methyl aminolevulinate (MAL) is
applied topically to the lesion.172,173 Although the porphyrin
porfimer can be administered systemically, systemic therapy
can be associated with prolonged photosensitivity.172,173 Several
hours after topical application of the porphyrin, the area is
exposed to visible light. The light penetrates the skin and is
selectively absorbed by the photosensitizer, which generates
reactive oxygen species. This in turn can cause lipid peroxida-
tion, protein crosslinking, increased membrane permeability,
and ultimately cell death. In addition to direct e ects on tumor
cells, PDT can damage blood vessels, resulting in impaired blood
flow, and can stimulate a vigorous local inflammatory reaction
that may contribute to tumor destruction.174
Response to PDT has been variable. Superficial lesions appear
to be most responsive to therapy with response rates ranging
from 72 to 100%.175,176,177,178 Three randomized controlled trials
(RCTs) with long-term follow-up have compared various PDT
protocols against simple SE for sBCC and primary nBCC. All
demonstrated statistically superior clearance rates with SE over
PDT.179 Side e ects from topical PDT include photosensitivity,
pain, erythema, edema, ulceration, and temporary pigmentary
change at the treated site. Healing is usually complete within
2 weeks and there is low probability of scarring.
3.9 Radiation Therapy
Radiation therapy (RT) is an option for the treatment of BCCs in
patients who are poor candidates for surgical intervention or in
patients with positive surgical margins. RT is usually adminis-
tered in a fractionated schedule to limit treatment-related side
e ects; however, it requires multiple sessions and strict compli-
ance ( Table 3.2). RT results in relative sparing of cosmetically
and functional tissues, its noninvasive and painless nature, and
its utility for many patients who are not candidates for surgical
intervention or for whom it is di cult to attain histologic clear-
ance. Unlike SE, RT does not provide histologic control of the
tumor margin. Most large series report overall 5-year cure rates
of 91 to 93% for previously untreated BCCs, with rates as high as
96% for smaller BCCs at low risk for recurrence.180,181,182 For
patients with recurrent BCCs, the reported cure rates are gener-
ally reported between 86 and 91%.180,181,182,183 BCCs that recur
following RT may behave more aggressively than those recur-
ring after surgical procedures, with higher rates of second
recurrence and distant metastasis.184
Short-term cutaneous side e ects of RT include erythema
and edema, scaling, vesicles, bullae, erosions, ulceration, pain,
and occasionally infection. Healing generally occurs within 3 to
4 weeks following the final treatment, but symptoms may per-
sist for months in severe cases. Other less common short-term
side e ects include a “comedo reaction,” which is a benign con-
dition characterized by the appearance of large, open come-
dones at the periphery of the treated areas.
Delayed e ects of radiation within the treatment field
include permanent alopecia that usually occurs within the
treatment field. Patients should be advised of this prior to treat-
ment, and pretreatment counseling is essential. Chronic radia-
tion dermatitis generally appears months to years following
therapy and is characterized by permanently mottled areas of
hypopigmentation and hyperpigmentation, a dry, hyperkera-
totic, atrophic, shiny epidermis, telangiectasias, and dermal
fibrosis. Severe dermal and subcutaneous fibrosis is an uncom-
mon consequence of RT for cutaneous malignancies.
Delayed radiation necrosis may develop months to years fol-
lowing RT, and is marked by spontaneous breakdown of the
skin within the treatment field, with erythema, erosions or
ulcerations, crusting, and discomfort. Radiation necrosis is usu-
ally precipitated by trauma, infection, or exposure to cold or
sunshine, and is secondary to poor vascularity and atrophy of
the previously irradiated area. Irradiation of cartilaginous and
bony structures such as the ear and nose may result in chon-
droradionecrosis or osteoradionecrosis, although this is uncom-
mon using modern techniques.185
Risk factors for secondary cancers after RT include higher
radiation doses, larger radiation fields, sun-exposed sites, fair
skin, and early age of radiation exposure. Increased fractiona-
tion with a smaller dose per fraction reduces this risk. Although
some investigators think that the risk of radiation-induced
cutaneous malignancy is much smaller using modern treatment
protocols, RT continues to be avoided in young people and in
those with genetic susceptibility to radiation-induced malig-
nancies.186 Incidental radiation exposure to other tissues can
also result in delayed complications, such as cataracts, infertil-
ity, and thyroid cancer. These are uncommon events that should
be avoided with proper shielding during therapy.
Table 3.2 Radiation therapy regimens for basal cell carcinoma
Tumor diameter

Margin

Electron beam
radiation therapy
<2 cm

1–1.5 cm

64 Gy in 32 fractions
over 6–6.4 wk
55 Gy in 20 fractions
over 4 wk
50 Gy in 15 fractions
over 3 wk
35 Gy in 5 fractions
over 5 d
>2 cm

1.5–2 cm

66 Gy in 33 fractions
over 6–6.6 wk
55 Gy in 20 fractions
over 4 wk
Postoperative adjuvant
Therapy
50 Gy in 20 fractions
over 4 wk
60 Gy in 30 fractions
over 6 wk
Treatment of Squamous and Basal Cell Carcinoma of the Skin
56

3.10 Intralesional Therapy
Intralesional therapies (interferons, 5-FU, or bleomycin) are
used infrequently for the management of BCC; however, these
therapies may have a place in modern regimens.187,188 A sys-
tematic review of open label studies, case series, and the few
randomized trials that have investigated the e cacy of intrale-
sional interferon for BCC found overall cure rates for interferon
beta, interferon alfa-2a, and interferon alfa-2b of 63, 68, and
76%, respectively.187 Data are limited on the use of intralesional
5-FU and bleomycin; however, the results of a few case reports
and small case series suggest that these therapies may be highly
e ective for BCC.189,190,191,192 Adverse e ects of intralesional in-
terferon, 5-FU, and bleomycin include local pain, erythema,
necrosis, and ulceration.187 Systemic side e ects are less likely
with intralesional injection than with systemic administration,
but may also occur. Risks of interferon therapy include fever,
malaise, headaches, myalgias, cytopenia, hepatotoxicity, and
nephrotoxicity. Pulmonary toxicity, cutaneous sclerosis, and
Raynaud phenomenon have been associated with bleomycin.
Gastrointestinal distress and cytopenias are potential adverse
e ects of 5-FU. Evidence is limited on the long-term e cacy of
intralesional therapies for BCC.
3.11 Targeted Therapy for BCC
Including LABCC and MBCC and
Hedgehog Pathway
BCCs that are extensive or invade below the dermis and poten-
tially vital structures are di cult to surgically clear without sig-
nificant morbidity. Many of these may become locally advanced
or metastasize. Although low, estimates of the metastatic rate
of BCC ranged from 0.0029 to 0.55%.193 In another report, the
population-based case mortality rate from BCC was approxi-
mately 0.05%.194 Men develop metastatic disease more fre-
quently than women, although the reason for this is unknown.
Metastatic lesions usually result from primary, deeply invasive,
or large lesions with an area of greater than 10 cm.2,193 The
most common sites for metastasis include the regional lymph
nodes, lungs, bones, skin, and liver.195
BCCs that metastasize to either local or distant lymph nodes
or distant organs would best be addressed through systemic
therapy. Together, these locally advanced or metastatic BCCs
comprise a disease group termed “locally advanced BCCs”
(LABCCs). While accurate estimates of the incidence of LABCCs
are di cult to obtain, in part due to the lack of widespread use
of a staging system by dermatologists and lack of uniform
reporting requirements for NMSCs, LABCCs are thought to rep-
resent roughly 1 to 10% of all BCCs, with metastatic BCCs
accounting for 0.0028 to 0.5%.196,197,198 From our clinical experi-
ence, patients presenting with LABCCs appear to fall into two
categories: those who present with LABCC due to delay in
accessing medical attention or those who have BCCs that are
intrinsically aggressive, are refractory, or recur after treatment.
Included in this group are those patients with chronic immuno-
suppression following organ transplant and some patients with
Gorlin’s syndrome. Therapeutic options for such patients are
limited.199,200
The Hedgehog pathway was initially identified as a critical
developmental regulator of embryonic segment polarity in
Drosophila in 1980.201 This and related developmental work
in fly body patterning was recognized by the Nobel Prize in
Physiology and Medicine in 1995. Vertebrate homologs of the
Drosophila Hedgehog ligand were first reported in 1993, and
definition of central components of the mammalian signaling
pathway followed in the late 1990s and early 2000s.202 The first
definitive linkage of mutation in this pathway to cancer, that is,
to development of BCC, was made in 1996.101,203
Hedgehog signaling regulates embryonic development ensur-
ing that tissues reach their correct location, size, and cellular
content. The Hedgehog pathway normally remains inactive in
adult tissues; however, reactivation of this pathway results in
malignant transformation and tumorigenesis.204,205 More than
90% of all BCCs have identified abnorm al Hedgehog pathway
signaling. There are two classic mechanisms of Hedgehog path-
way reactivation: mutation-driven signaling (ligand independ-
ent) and abnormal signaling in the tumor microenvironment
(ligand dependent).94 In mutation-driven signaling, tumor cells
harbor mutations in key components of the Hedgehog pathway
allowing for independent activation of the biomolecular system
and subsequent stimulation of unregulated proliferation.206 In
ligand-dependent activation, tumor cells overexpress Hedgehog
ligands that activate surrounding stromal cells leading to
uncontrolled growth.207 Mutations in two major receptor pro-
teins, Patched-1 (PTCH1) and Smoothened (SMO), may result in
abnormal activation of the Hedgehog pathway and are the focus
of proposed interventions.
As shown in Fig. 3.24, Hedgehog pathway activation occurs
via binding of an extracellular Hedgehog ligand (Shh) to PTCH1,
a transmembrane receptor. Once bound, PTCH1 is internalized
and degraded, allowing for release of a the transmembrane pro-
tein SMO from the inhibitory e ect of PTCH1.111 SMO can then
move from the intracellular compartment to the cell membrane
of the cilium and activate the GLI family of transcription factors.
Activated GLI factors enter the nucleus and initiate the tran-
scription of target genes.111 The majority of sporadic BCCs con-
tain mutations that result in inactivation of PTCH1, with
subsequent constitutional activation of SMO.208 Inhibition of
SMO activation, either through appropriate PTCH hindrance or
through new SMO inhibitors such as vismodegib (Erivedge,
Genentech), prevents unregulated proliferation.
Basal cell carcinoma (BCC), medulloblastoma, rhabdomyosar-
coma, and other human tumors are associated with mutations
that activate the proto-oncogene Smoothened (SMO) or that
inactivate the tumor suppressor Patched (PTCH). Smoothened
and Patched mediate the cellular response to the Hedgehog
(Hh) secreted protein signal, and oncogenic mutations a ecting
these proteins cause excess activity of the Hh response
pathway.
The story of how the first inhibitor of the Hh pathway,
cyclopam ine, was discovered is one of the m ost fascinating
in biom edicine. In the late 1950s, pregnant ewes were found
to produce one-eyed o spring, or extrem e holoprosence-
phaly199,209( Fig. 3.25).
In the 1970s, the active agent inducing these changes, cyclop-
amine, was isolated and its structural formula identified. Subse-
quent studies in the 1990s in chick embryos demonstrated
cyclopamine’s ability to induce holoprosencephaly and to bind
Treatment of Squamous and Basal Cell Carcinoma of the Skin
57

the transmembrane protein, Smoothened.210 Subsequently, a
number of analogues were developed by modifications to
cyclopamine to improve solubility, and oral bioavailability. Col-
lectively, these analogues are called Smoothened inhibitors
(SIs), due to their targeting of the Smoothened protein.
In 2000, Taipale et al showed that cyclopamine inhibits the
Hh response and was a potential “mechanism-based” therapeu-
tic agent for treatment of some tumors. They showed that
cyclopamine or synthetic derivatives with improved potency,
block activation of the Hh response pathway, and abnormal cell
growth associated with both types of oncogenic mutation. Their
results also indicated that cyclopamine could act by influencing
the balance between active and inactive forms of SMO.211,212,213
This discovery, together with rapidly accumulating evidence
implicating the Hh pathway in oncogenesis, led to focused
e orts by multiple biotechnology and pharmaceutical compa-
nies to develop cyclopamine derivatives with improved phar-
macologic properties or to develop agents that e ectively
outcompeted cyclopamine for binding to the critical cell-surface
activator of Hh signaling, the 7-transmembrane G-protein-
coupled–like receptor, SMO. Vismodegib is a member of this
class: structurally unrelated to cyclopamine but able to bind
with high a nity and specificity to SMO, leading to potent sup-
pression of Hh signaling in reporter systems and in a preclinical
model of Hh-dependent disease.214 An Investigational New
Drug application for vismodegib was filled with the FDA in Sep-
tember 2006, leading to launch of a first-in-human phase I clin-
ical trial at three U.S. sites in January 2007.
Multiple orally available smoothness inhibitors are currently
in human clinical trials against BCCs. The first and only U.S.
FDA-approved SI for advanced BCCs (aBCCs) to date is vismode-
gib, which became commercially available in 2012. The phase II
study with 96 aBCC patients leading to FDA approval demon-
strated an independently assessed response rate of 30% in
patients with metastatic BCC and 43% response rate in
LABCC.215 A subsequent study of 119 aBCC patients showed
similar findings.216 The availability of vismodegib as highly tar-
geted therapy for aBCCs is one of the greatest success stories in
translational medicine.
Initial investigation of Vismodegib documented its therapeu-
tic e ects in both in vitro studies with downregulation of GLI1
by approximately 90% compared to controls and in ex vivo anal-
ysis with reported downregulation of GLI1 by greater than 50%
in skin biopsy specimens excised from treated patients.214,217 A
phase 1 trial with vismodegib included 68 patients with solid
tumors, of which 33 had aBCC, 8 had pancreatic cancer, 1 had
medulloblastoma, in addition to 17 other types. The overall rate
of complete or partial response was 58% with specific response
of 50% in patients with metastatic BCC and 60% in patients with
Fig. 3.25 In the decade after World War II, Idaho farmers noticed that
a random batch of their lambs was being born with strange birth
defects. The creatures had underdeveloped brains and a single eye
planted, Cyclops-like, in the middle of their foreheads. In 1957, they
called in scientists that worked for 11 years to solve the mystery: corn
lilies. When the animals moved to higher ground during droughts, they
snacked on the flowers. The lilies, it turned out, contained a poison,
later dubbed cyclopamine that stunted developing lamb embryos. The
adult mothers remained unharmed. The case of the cyclopamine and
the one-eyed Idaho lambs remained a freakish chemistry footnote for
the next three decades.
Fig. 3.24 Simplified schematic of common
mutations in the Hedgehog signaling pathway
leading to basal cell carcinoma from pathway
activation. (Reprinted with permission from
Sheridan C. Genentech obtains proof of concept
for hedgehog inhibition. Nat Biotechnol
2009;27:968–969.)
Treatment of Squamous and Basal Cell Carcinoma of the Skin
58

LABCC.217 Despite vast heterogeneity with respect to tumor his-
tology, patient characteristics, and dosing concentrations, vis-
modegib was generally well tolerated with 8.8% experiencing a
grade 4 event (hyponatremia, fatigue, pyelonephritis, presyn-
cope, resectable pancreatic adenocarcinoma, and paranoia with
hyperglycemia), and 27.9% of patients experienced a grade 3
event (hyponatrem ia [10.3%], abdominal pain [7.4%], and fa-
tigue [5.9%]).
A multicenter, nonrandomized phase 2 clinical trial of vismo-
degib in 104 patients was conducted from February 2009
through November 2010.215 Of the 33 patients with metastatic
BCC, 10 (30%) had a response as judged by independent review,
and 15 (45%) had a response as judged by site investigators. In
the 63 patients with LABCC, 38 (60%) had at least a partial res-
ponse as judged by site investigators, with 13 (21%) judged to
have a complete response with verification established by the
absence of residual disease on biopsy.218
An additional phase 2 trial was conducted in 41 patients with
basal cell nevus syndrome (BCNS).219 Vismodegib was associ-
ated with a decrease in the number of new and existing surgi-
cally eligible BCCs with surgically eligible BCCs occurring at a
rate of 2 per year in the vismodegib group compared with
29 per year in the control group (p <0.001). There was also a
significantly greater decrease in the size of existing surgically
eligible BCCs in patients receiving vismodegib (65% in the vis-
modegib group vs. 11% in the control group; p =0.003).218
Current research and clinical trials focusing on the adminis-
tration of synthetic SMO inhibitors, or Hh pathway inhibitors,
for patients with locally advanced and metastatic basal cell car-
cinoma (MBCC) are ongoing.220,221 Clinical trials have shown
exceptional decrements in tumor burden as well as resolution
of metastatic disease with the drug as the sole treatment
modality, thus reducing the need for SE and associated morbid-
ity and mortality.218 Furthermore, recent case reports have
documented the use of vismodegib as a potential neoadjuvant
therapy prior to surgical or radiotherapeutic intervention.216,
222,223
Although ongoing clinical trials for topical and systemic
therapies are currently pending, vismodegib remains the only
FDA-approved Hh pathway inhibitor approved for the treat-
ment of metastatic and LABCC.224
More recently, evolving treatment protocols have led to novel
algorithms of treatment under clinical trial settings. Targeted
therapy with Hh inhibitors including vismodegib has served as
both a viable alternative and adjunct to SE alone in the author’s
practice. As example we present data of our first consecutive
series of 20 patients initially treated from April 2012 to June
2013. All adult patients with locally advanced basal cell carci-
noma (LABCC) and/or recurring or MBCC who were not candi-
dates for surgery or RT (due to clinical morbidities or patient’s
refusal of surgery/RT) received vismodegib 150 mg once a day
until disease progression, unacceptable side e ects, or discon-
tinuation of treatment at patients’ request. The peak plasma
concentration of vismodegib is reached 48 hours after oral
administration and maintained for 72 hours, formulating the
currently recommending schedule of 150-mg PO daily.217,225
LABCC was defined as at least one lesion 20 mm or more in
areas of limited tissue availability (eyelid, ear, nasal ala, etc.);
patients that had recurrence after two or more surgical
procedures and curative resection was unlikely and surgery
was expected to result in substantial morbidity and/or
deformity.
Response was defined as a decrease of ≥30% in the externally
visible or radiographic dimension or complete resolution of
ulceration if present at baseline. Radiographic imaging was
obtained for all patients with MBCC and for patients with
LABCC who had radiographically measurable disease. Objective
response of vismodegib on tumor regression and prevention of
disease progression was visually and clinically appreciable in
almost all treated patients. As of the data-cuto point 13/20
(65%) patients had complete response (defined as the absence
of residual BCC on assessment of a biopsy specimen) and 7/20
(35%) patients had partial response. As of the data-cuto point,
13 of the 13 patients who had a complete response did not have
disease progression ( Fig. 3.26 and Fig. 3.27). One patient
was excluded from treatment on his request due to unaccept-
able side e ects (loss of taste and muscle cramps). Most com-
mon side e ects were loss of taste (100%), muscle spasms
(80%), hair loss (50%), weight loss (30%), and fatigue (10%). Once
treatment stopped, the side e ects subsided. Surgery was per-
formed in the seven patients who had partial response. Minimal
residual tumor was identified in five of them and no residual
tumor was found in two of the patients.
In Fig. 3.27a, marked resolution of the tumor with reduc-
tion in vertical height and surrounding erythema was evident
by day 30 of treatment. By day 120, there were no palpable
lesions and the surrounding erythema and induration associ-
ated with the metastatic lesion had been greatly diminished.
Radiographically, the patient had exceptional regression of
tumor burden matching the clinical picture. The chemothera-
peutic agent not only benefited the cutaneous manifestations of
disease, but also had a profound e ect on systemic metastases
as shown in Fig. 3.27b. By day 120, the patient with cutane-
ous lesions ( Fig. 3.27) had radiographic evidence of complete
resolution of pulmonary metastases.
In this series of 20 consecutive patients, vismodegib showed
encouraging results with objective response rate superior to
90% and provided substantial clinical benefit for the selected
patients. However, treatment patterns, clinical outcomes,
health care resource use, and definitions of advanced and com-
plex/di cult-to-treat disease are not uniformly adopted in the
literature and clinical practice.
Itraconazole, an antifungal agent, has also been identified as
a potent inhibitor of the Hh signaling pathway.226 In a phase II
trial including 29 patients with sporadic BCC>4 mm, 15 patients
were treated with 200 mg twice daily for 4 weeks prior to
surgery and 4 patients with 100 mg twice daily for 1 to
4 months (mean 2.3 months).227 Itraconazole reduced tumor
size by 24% and promoted re-epithelialization in 8 patients with
a total of 57 tumors. Further data from more robust trials are
pending; however, itraconazole may play a role in vismodegib-
resistant subjects or in BCC prevention.
3.12 Surgical Management
Surgical options for BCCs at low risk for recurrence include
electrodesiccation and curettage (ED&C), conventional SE, and
Treatment of Squamous and Basal Cell Carcinoma of the Skin
59

cryosurgery. Cryosurgery is infrequently used for this indica-
tion and ED&C is mainly used by dermatologists and primary
care physicians.
3.12.1 Electrodesiccation and Curettage
The procedure of curettage and electrodesiccation is used most
often for the treatment of selected small basal cell carcinomas
(BCCs) and squamous cell carcinomas (SCCs). It is a deceptively
simple procedure that requires proper selection of tumor and a
skilled practitioner. Otherwise, the recurrence rate is unaccept-
ably high. The tumor is prepared and anesthetized with a local
anesthetic. The curette, an oval instrument with a cutting edge,
is used to remove the soft cancerous skin. The tumor margins
are determined by “feel,” with normal skin having a firm and
gritty consistency. After curettage, the base and borders of the
wound are electrodesiccated to destroy residual tumor and to
provide hemostasis. The wound heals by secondary intention in
2 to 3 weeks.
Although ED&C is a fast and easily performed treatment for
BCC, the procedure does not include histologic confirmation of
tumor removal and is not appropriate for BCCs with clinical or
histologic features that suggest an elevated risk for tumor
recurrence. The expected unpleasant cosmetic results of ED&C
(a round hypopigmented scar) also should be considered during
treatment selection. Curettage and electrodesiccation (C&E) is
the process of alternatively scraping away tumor tissue with a
curette down to a firm layer of normal dermis and denaturing
the area by electrodessication. Up to three cycles may be per-
formed in a session. Although a fast and cost-e ective
technique for superficial lesions, it does not allow histologic
margin assessment. Overall 5-year cure rates reported for BCC
and SCC are 92% and 96%, respectively.228 However, recurrence
rates can be high for high-risk locations (21%) and high-risk
histologic subtypes (27%).
This technique is deemed e ective for low-risk tumors if fol-
lowing distinct criteria. First, this technique should not be used
to treat areas with terminal hair growth due to the risk that a
tumor extending down follicular structures might not be
adequately removed. Second, if the subcutaneous layer is
reached during the curettage, SE should be performed. Third, if
curettage has been performed based only on the appearance of
a low-risk tumor, biopsy results of the tissue taken at the time
of curettage should be reviewed to make sure that there are no
high-risk pathologic features that would require additional
therapy.
3.12.2 Surgical Excision
SE is the gold standard and used for the treatment of both BCCs
at low or high risk for recurrence. Data on the e cacy of SE for
BCC are primarily limited to retrospective case series and
randomized trials.180,229,230,231,232 Because SE of BCCs with 4 to
5 mm margins has been associated with 5-year cure rates
exceeding 95%,180,229,230,231,233 it remains the most commonly
practiced technique. Currently, 4-mm surgical margins are
commonly used for the excision of these lesions. The results of
a 2010 meta-analysis of published studies on conventionally
excised BCCs that excluded studies of previously excised, irradi-
ated lesions, or morpheaform BCCs confirmed that rates of
Fig. 3.26 Locally advanced basal cell carcinoma involving the ear. Response after 1 and 4 months of treatment. Biopsy sites after 8 months of
treatment and pathology showing absence of tumor in all sites. Patient remains without evidence of disease 1 year after discontinuing treatment.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
60

pathologically confirmed complete excisions were similar for
surgical margins between 3 and 5 mm.234 The e cacy of con-
ventional excision of BCCs in higher risk areas of the face and
head is substantially smaller than in lower risk BCCs, with cure
rates ranging from 83 to 92%.180,229,230,235,236 Most commonly,
this is thought to result from incomplete margin assessment
and avoidance of large excisions in cosmetically sensitive areas.
This topic will be further discussed in the surgical management
of the high-risk BCCs.
Conventional SE can be performed faster than Mohs surgery,
is relatively inexpensive if frozen sections are not performed,
and provides pathologic confirmation of surgical margins and
specimens (Fig. 3.28 and Fig. 3.29). Excision is typically per-
formed in an outpatient setting under local anesthesia and is
Fig. 3.27 (a) Sixty-seven-year-old female with locally advanced and metastatic basal cell carcinoma (MBCC) to the lungs. Primary locally advanced
tumor presented with MBCC treated with invasion into the right scapula. Patient entered Vismodegib treatment protocol with 150 mg/d. Responses
on follow-up at days 30 and 120 are shown. No surgical excisions were required. Radiographic image evidence of tumor regression. Scouting biopsies
negative for residual BCC. (b) Same patient with complete resolution of lung metastases between 120 days of treatment with targeted therapy.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
61

usually well tolerated; however, depending on the size and
location of the lesion, general anesthesia may be required. The
long-term cosmetic and functional results of both methods are
usually superior when compared with RT. The surgical defect
typically is immediately repaired by either intermediate or
complex closure, use of adjacent tissue flaps, skin grafts, or,
more rarely, distant tissue flaps. This allows wound healing to
be completed within 1 to 2 weeks. If primary closure is not pos-
sible, healing can take place by secondary intention. The type of
closure depends upon several factors including the size, depth,
and location of the defect, the availability and laxity of nearby
tissue, and patient and physician preference.
It is important to point out that surgical excision (SE) is inva-
sive and variable amounts of normal, uninvolved tissue may be
sacrificed to achieve acceptable cure rates. In some anatomic
areas, functional and/or cosmetic deficits may be produced.
In a retrospective study, 1,832 BCCs were excised from
1,329 patients.237 Two hundred and fifty one (14%) lesions were
incompletely excised with 135 (7.4%) involving the peripheral
margin only, 48 (2.6%) the deep margin only, and 41 (2.2%)
involving both. Nasal location was the most common predictor
of incomplete excision.237 Spontaneous regression of BCC may
occur after incomplete excision; the identification of residual
tumor in re-excision tissue specimens has been reported in 14
to 69% of specimens, and rates of clinical recurrence after
incomplete excision range from 0 to 44% (mean 27%).234,238
Thus, management of these incompletely excised lesions is con-
troversial. In patients who do not undergo immediate
Fig. 3.28 Morpheaform basal cell carcinoma pre-excision- and postexcision after complete circumferential peripheral and deep margin assessment
(CCPDMA) and reconstruction with a split thickness skin graft.
Fig. 3.29 Morpheaform basal cell carcinoma pre-excision and postexcision after Mohs micrographic surgery and reconstruction with cutaneous flaps.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
62

treatment for positive margins, lesion recurrence may be
delayed. Although the majority of recurrences of scalp, superfi-
cial, or keratotic BCCs appear to occur within 2 years, BCCs may
recur after longer periods.239
Due to the risk for lesion recurrence, a thorough discussion of
the risks and benefits of treatment with all patients with
incompletely excised BCCs is prudent. Factors such as patient
preference, tumor morphology and location, presence or
absence of aggressive clinical and pathologic features, morbid-
ity of delayed additional surgery, and patient tolerance for an
additional procedure influence the decision of whether to pro-
ceed with additional therapy and a ect the choice of treatment.
For most patients, incompletely excised lesions can be managed
with conventional SE or Mohs surgery. Less frequently, RT is
utilized. Mohs surgery is preferred for the management of
incompletely excised BCCs with features associated with a high
risk for recurrence and lesions on the head or neck due to the
advantage of intraoperative margin control and tissue sparing.
Conventional surgical re-excision is an appropriate option for
incompletely excised low-risk lesions on the trunk or extrem-
ities. Patients with incompletely excised lesions that are not
surgically amenable or who are not candidates for additional
surgery can be treated with radiation. Close clinical follow-up is
warranted for patients who choose to defer treatment for
incompletely excised lesions. Patients should be evaluated at
least every 3 to 6 months for the first 2 years after treatment,
and then at least once or twice per year. More frequent follow-
up may be appropriate, depending on the clinical scenario.
Surgical management of high-risk BCCs should be done by SE
with complete circumferential peripheral and deep margin
assessment (CCPDMA) with frozen or permanent section or
through the Mohs micrographic technique (Mohs micrographic
surgery [MMS]; Fig. 3.30).
SE involves removing the visible parts of the tumor along
with a margin of normal-looking tissue around the tumor to
remove all clinically invisible tumor extension and has been
discussed in the surgical management of low-risk BCC. In order
to select the most appropriate surgical alternative for the pa-
tient, it is extremely important that the surgeon understand
the multiple histologic grossing techniques and their
implications.
MMS is generally accepted as the gold standard for areas in
which tissue sparing is functionally or cosmetically essential.
This has been quantified in one pilot randomized controlled
trial (RCT) that though it did not meet inclusion criteria, it
found a median defect size 1.6 times greater with SE than with
MMS.240 Mohs surgery should be reserved for lesions that
exhibit features associated with an elevated risk for recurrence
and for situations in which tissue sparing is of great value due
to cosmetic or functional concerns. The procedure is not indi-
cated for small primary BCCs on the trunk or extremities that
lack aggressive clinical or histopathologic features because
other procedures have similar e cacy and are less time-con-
suming and less costly.
Excision with comprehensive intraoperative margin control
is in our opinion the preferred surgical technique for high-risk
BCC. These include either excision with CCPDMA with frozen
section or Mohs micrographic technique. However, if standard
excision with POMA is used for treatment of a high-risk tumor
due to patient-related clinical circumstances or other variables,
Fig. 3.30 Tubingen rush-fixed paraffin technique
of three-dimensional histology. The complete
circumferential peripheral and deep margin
assessment (CCPDMA) with permanent sections
excision technique used in our service involves
separating the outside rim of presumptively
normal tissue, the deep margin, and the tumor
itself, followed by examination of all parts by a
pathologist. This helps localize tumor strands in
three dimensions. (Adapted from Moehrle M,
Dietz K, Garbe C, Breuninger H. Conventional
histology vs. three-dimensional histology in len-
tigo maligna melanoma. Br J Dermatol
2006;154:453–459.)
Treatment of Squamous and Basal Cell Carcinoma of the Skin
63

wider surgical margins than those recommended for low-risk
lesions must be taken and increased recurrence rates should be
expected.241 It is also important to remember that with the
standard approach (i.e., non-CCPDMA), the specimen’s histolog-
ical margins are evaluated by a bread-loafing technique that,
although allows great visualization of the tumor and surgical
margins of the studied section, does o er only a sample evalua-
tion of the real surgical margin (approximately 1–2%;
Fig. 3.31 and Fig. 3.32; Table 3.3).
3.12.3 Cryosurgery
Cryosurgery is infrequently used for the treatment of BCC. This
technique uses liquid nitrogen to freeze the tumor. Destruction
of the lesion results from the formation of extracellular and
intracellular ice crystals, hypertonic damage, disruption of the
cellular phospholipid membrane, and vascular damage through
vascular stasis.242 Cryosurgery is cost-e ective and requires
minimal anesthesia; however, this technique is contraindicated
for lesions with features associated with a high risk for recur-
rence, concern of a poor cosmetic outcome, and patients with a
physiologic intolerance to cold. Reported cure rates using cryo-
surgery vary widely for primary BCCs, although some series
report 5-year recurrence rates for primary and recurrent BCCs
are approximately 8 and 13%, respectively.243,244,245,246 Most
commonly, cryotherapy may result in permanent hypopigmen-
tation or scarring.
3.13 Squamous Cell Carcinoma
Classically, patients with invasive SCC present with a persistent
ulcer or nonhealing wound. In addition, the clinical appearance
of SCC is largely influenced by the level of di erentiation of the
lesion. Well-di erentiated SCC classically presents as thick,
scaly papules and plaques. By contrast, poorly di erentiated
SCC is often soft, nonscaly, ulcerated, or hemorrhagic.
The presenting symptoms and clinical presentation of inva-
sive SCC are location specific and highly variable. Numbness,
tingling, and muscle weakness may reflect underlying perineu-
ral involvement. These and other neurologic symptoms must be
fully evaluated as they may generally influence prognosis.247
SCC that is induced by human papillomavirus (HPV) most
commonly manifests as a new or enlarging warty grow th on
the penis, vulva, or perianal or periungual region. Patients often
present with a history of warts that have been refractory to var-
ious treatment modalities in the past. A history of previously
documented genital HPV infection is usually elicited.248,249
Lesions may range in size from less than 1 to greater than 5 cm,
depending on the histologic type and delay in presentation.
3.14 Premalignant Lesions
Certain potentially precancerous grow ths, or precancers, most
of them resulting from cumulative sun damage, have been
Fig. 3.31 Margin evaluation of a conventional surgical excision. Conventional surgical excision without complete circumferential peripheral and deep
margin assessment (CCPDMA) uses “bread loaf” vertical sectioning, which only permits the evaluation of a small portion of the tumor margins and
may increase the chance for false negatives.
Fig. 3.32 Mask area of the face. Lesions in specific locations on the face
have higher risk to recur. The H region, depicted in the figure, is also
known as the mask area of the face and includes the central face, the
periorbital regions, the nose, lips, and chin as well as the preauricular and
postauricular skin. These areas are known to have higher recurrence rate
and thus smaller lesion sizes are still considered higher risk.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
64

associated with the later development of SCC. These lesions
may also serve as a potential marker for higher risk patients
with the necessity for increased or more frequent surveillance.
3.14.1 Actinic Keratosis
Up to 60 to 80% of cSCC tumors arise in association with prema-
lignant actinic keratosis (AK).250,251,252,253,254 These rough, scaly,
slightly raised grow ths or plaques, ranging in color from brown
to red and from about 1 mm to 1 inch in diameter, are found on
sun-exposed areas of the body, most often in older people
(Fig. 3.33, Fig. 3.34, Fig. 3.35, Fig. 3.36). They can be the
first step on the road to SCC, and some experts even consider
them the earliest form of SCC. Features of AK that are associated
with malignant transformation include inflammation, diame-
ter >1 cm, rapid growth, ulceration, bleeding, and erythema.250,
251,252,253,254 AKs are often palpable before becoming visible, and
can be felt by running your fingers over sun-exposed areas; this
can provide an early sign of their development. Anywhere from
2 to 10% of untreated AKs advance to SCC, in as rapid as
2 years.250,254 The more AKs that go untreated and the older
these lesions are, the greater the chance that one or more may
develop into invasive SCC. A cutaneous horn is a clinical variant
of AK that presents as a hyperkeratotic protuberance shaped
like a cone extending above the plane of the skin (Fig. 3.37).
Histologically, they appear to have a compact proliferation of
keratin. Approximately 15% of cutaneous horns actually contain
cSCC, and excision is indicated.255,256,257
3.14.2 Squamous Cell Carcinoma in the
Base of Cutaneous Horn
Similar to SCC, the major risk factors for the development of
AKs include chronic sun exposure, fair skin, advancing age, and
male sex. UV radiation is believed to contribute to the develop-
ment of AK through the induction of mutations in epidermal
keratinocytes that lead to increased survival and proliferation
of atypical cells.258 Ongoing and regular use of sunscreens
reduces the development of these lesions.45,259
AKs most commonly present as scaly, erythematous macules
or papules on sites of chronic sun exposure such as the scalp,
face, lateral neck, dorsal forearms, and dorsal hands. In particu-
lar, men with severe baldness were approximately seven times
more likely to have 10 or more AKs than men with minimal or
absent baldness.260
Distinguishing AK from SCC can be challenging, as both disor-
ders commonly present as erythematous, scaly papules on
sun-exposed areas. The diagnosis of AK is often made based on
visual and tactile clinical inspection. Biopsy is indicated if the
diagnosis is uncertain; a common indication for biopsy is dis-
tinguishing AK from SCC. In particular, lesions that are greater
than 1 cm in diameter, indurated, ulcerated, or rapidly grow-
ing and lesions that fail to respond to appropriate therapy
should be considered for biopsy. Estimates of annual rates of
transformation from AK to SCC have ranged from 0.03 to
20%.261,262,263,264
3.14.3 Leukoplakia
These white patches arising from the mucous membranes of
the tongue, gums, cheeks, or elsewhere inside the mouth have
the potential to develop into SCC (Fig. 3.38 and Fig. 3.39).
They may be caused by sources of chronic irritation, such as
habitual alcohol consumption or tobacco use, or rough edges on
teeth or dentures. Leukoplakia (actinic cheilitis) on the lips,
however, is mainly caused by sun damage.
Table 3.3 National Comprehensive Cancer Network (NCCN) criteria for
high-risk basal cell carcinoma lesions
Low risk

High risk
Location/size

Area L<20 mm

Area L>20 mm
Area M<10 mm

Area M>10 mm
Area H<6 mm

Area H>6 mm
Borders

Well defined

Poorly defined
Primary versus
recurrent
Primary

Recurrent
Immunosuppression

(–)

(+)
Site of prior radiation
therapy
(+)

(–)
Pathology subtype

Nodular, superficial

Aggressive growth
Perineural
involvement
Perineural involvement (–)

(+)
Notes: Area H= “mask areas” of face ( Fig. 3.32; central face, eyelids,
eyebrows, periorbital, nose, lips [cutaneous and vermilion], chin,
mandible, preauricular and postauricular, temple, ear), genitalia, hands,
and feet.
Area M= cheeks, forehead, scalp, neck, and pretibia.
Area L= trunk and extremities (excluding pretibia, hands, feet, nail units,
and ankles).
Fig. 3.33 Hypertrophic actinic keratosis. The hypertrophic type has a
thick adherent scale on top of an erythematous base.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
65

Fig. 3.34 (a) Actinic keratosis with typical fea-
tures of scaling with erythematous base. (b)
Pigmented actinic keratosis of the left temple.
Fig. 3.35 Numerous actinic keratoses of the face.
Fig. 3.36 Extensive ultraviolet damage with coalescing hypertrophic
actinic keratoses.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
66

Oral leukoplakia is a precancerous lesion that presents as
white patches or plaques of the oral mucosa. It represents
hyperplasia of the squamous epithelium, thought to be a step in
the transformation to dysplasia, to carcinoma in situ, to invasive
malignant lesions. Leukoplakia is also seen in purely inflamma-
tory conditions not associated with malignancy. An association
exists between leukoplakia and HPV.265
Between 1 and 20% of leukoplakia lesions will progress to
carcinoma within 10 years.266 The clinical significance and nat-
ural history of oral leukoplakia depends upon the presence and
degree of dysplasia.266,267 Leukoplakic lesions that arise in
trauma-prone regions of the oral cavity (cheek, dorsum of
tongue) show evidence of dysplasia less often than do lesions in
areas where the mucosal is normally thin (ventral tongue, ret-
romolar triangle). In these regions of thin mucosa, carcinogen
exposures are thought to contribute more significantly to
malignant transformation than mechanical trauma. Risk factors
for oral leukoplakia are similar to that of SCC, and avoidance of
such is of primary importance. Any suspicious lesions should be
biopsied to rule out carcinomatous changes.
3.14.4 Actinic/Solar Cheilitis
Actinic or solar cheilitis is a premalignant lesion of the lip simi-
lar to AK, thought to be caused most commonly by chronic sun
exposure.268,269 It is most common in geographic areas with
hot, dry climate, in outdoor workers, and in light-skinned indi-
viduals.269 Other risk factors for actinic cheilitis include older
age, male sex, tobacco use, and genetic conditions associated
with increased susceptibility to solar damage.269 While actinic
cheilitis shares a common pathogenesis with AK, the risk of
progression to SCC appears to be higher for actinic cheilitis than
for AK.269
Fig. 3.38 Gum leukoplakia: white patch that develops in reaction to
chronic irritation of the mucous membranes of the mouth.
Fig. 3.37 (a) Squamous cell carcinoma (SCC) arising in the base of cutaneous horn. (b) Cutaneous horn requiring biopsy to rule out SCC.
Fig. 3.39 Sublingual leukoplakia from the oral mucosa.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
67

Pictures in Fig. 3.40 typically presents as a persistent area
of dryness and scaling on the lower lip. Atrophy of the lip,
edema, erythema, ulceration, and destruction of the vermilion
border may be seen in more advanced lesions.269 Lesions are
usually solitary, but multiple lesions can occur. On palpation,
actinic cheilitis has a characteristic “sandpapery” feel to the
touch.
The diagnosis of actinic cheilitis is usually clinical. The pres-
ence of findings concerning for SCC and warrants biopsy and
histopathologic examination. Histopathology findings often
include acanthosis, hyperkeratosis, focal areas of atrophy, and a
variable degree of keratinocyte atypia.270 Solar elastosis is a fre-
quent secondary finding.
The choice of treatment in the individual patient is based
upon the extent and severity of the disease and patient prefer-
ence. The treatment options for actinic cheilitis include destruc-
tive therapies (liquid nitrogen, electrodessication, chemical
destruction, laser therapy, PDT, dermabrasion), topical medica-
tions (topical fluorouracil, imiquimod, retinoids, diclofenac),
and surgery.268,270,27,1,27,2,27,3,27,4,275
For isolated lesions of mild to moderate actinic cheilitis, cryo-
therapy with liquid nitrogen may be used (Fig. 3.40). In cases
of incomplete clearance, retreatment after 6 to 8 weeks fol-
lowed by a topical therapy as noted below may be undertaken.
Adverse e ects of cryotherapy include pain, edema, and scar-
ring. For multifocal or di use mild to moderate actinic cheilitis,
topical therapy with fluorouracil 5% cream is generally indi-
cated. The cream is applied twice a day for 2 to 4 weeks as tol-
erated. Typical adverse e ects include pain, erythema, edem a,
erosions, and ulcerations.273
Alternatively, topical imiquimod or diclofenac may be used
for multifocal or di use mild to moderate actinic cheilitis, with
e cacy and adverse reactions similar to fluorouracil. Of note,
diclofenac 3% gel may cause less irritation than topical fluoro-
uracil or imiquimod, but treatment duration extending to sev-
eral months may be necessary.276,277
For patients with severe actinic cheilitis (Fig. 3.41), evi-
dence of high-grade dysplasia, or inadequate response to topical
therapy, surgery (vermilionectomy) remains the mainstay of
treatment.278 SE allows the histopathologic examination of the
entire vermilion and detection of occult SCC. Common
postoperative complications from excision and reconstruction
include wound dehiscence, partial flap necrosis, scarring, and
loss of normal lip contour.278,279
3.14.5 Bowen’s Disease
This is an early, noninvasive stage of SCC. As shown in
Fig. 3.41, Fig. 3.42, Fig. 3.43, Fig. 3.44, Fig. 3.45, it
appears as a well-demarcated, persistent, often erythematous,
scaly patch or plaque that may resemble psoriasis or eczema
but can also be skin colored or pigmented. It tends to grow
slowly, enlarging over the course of years. If untreated, it may
become invasive. Bowen’s disease is most often caused by expo-
sure to the sun or to arsenic, but radiation and other chemical
carcinogens, genetics, and trauma also may play a role. The
HPV, highly transmissible through sexual contact, has been
documented as a cause of one form of Bowen’s disease a ecting
the genitals (Fig. 3.46). HPV can also arise in the mucous
membranes of the nose and mouth as well as on the skin
(Fig. 3.47). The FDA approved an HPV vaccine for use by
females aged 9 to 26 in 2006, and one for 9- to 26-year-old
males (as well as another vaccine for females) in 2009. The vac-
cines are considered highly e ective in preventing HPV and
thereby reducing the risk of both genital warts and cervical can-
cer as well as Bowen’s disease.
3.15 Squamous Cell Carcinoma
Risk Factors
3.15.1 Risk Overview
The predominant risk factor for both cSCC and BCC is intense
sunlight and sun exposure. As a general rule, people with fair
skin (Fitzpatrick skin types I–II), light hair, and blue, green, or
gray eyes with a history of substantial sun exposure are at high-
est risk of developing a cutaneous malignancy.7,66,280 Chronic
and cumulative sun exposure is the prevalent risk factor for
cSCC, and both UVA and UVB are implicated in tumor
Fig. 3.41 Actinic cheilitis. This disorder typically presents on the lower
lip as a persistent rough or scaly area. Patients often complain of a
constantly dry lip. Actinic cheilitis may involve only a small portion of
the lip or the entire lower lip. Fissuring or ulceration may also occur.
Fig. 3.40 Actinic cheilitis. Actinic keratosis present on the lip are
defined as actinic cheilitis.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
68

pathogenesis. The sun protection factor (SPF) in sunscreens,
however, only measures protection against UVB, with no
known safe limit of sun exposure. The incidence of cSCC
increases significantly with age, likely reflecting an increased
cumulative exposure to sunlight. Those whose occupations
require long hours outdoors or who spend extensive leisure or
recreation time in the sun are in particular jeopardy.281 Anyone
who has had BCC is also more likely to develop a recurrence or
primary cSCC. Other environmental risk factors for cSCC include
a history of radiation, chronic inflammation (as in Marjolin’s
ulcer), and exposure to arsenic and hydrocarbons. Chronic
immunosuppression resulting from either acquired immunode-
ficiency syndrome or systemic drugs required for most trans-
plant recipients markedly increases the risk of cSCC up to 250
times the general population and is closely correlated to the
type of transplant, immunosuppressive drug burden, and the
cumulative time since transplantation.282,283,284 UV-induced
mutations in the p53 tumor suppressor gene are thought to be
the molecular mechanism of malignant transformation of kera-
tinocytes285,286. Other risk factors for SCC include previous his-
tory of nonmelanoma skin cancer (NMSC), a family history of
Fig. 3.42 Bowen’s disease. Bowen’s disease is considered an early,
noninvasive stage of squamous cell carcinoma. It appears as a
persistent red-brown, scaly patch that may resemble psoriasis or
eczema. Bowen’s disease is most often caused by exposure to the sun
or to arsenic, but radiation and other chemical carcinogens, genetics,
and trauma also may play a role.
Fig. 3.43 Bowen’s disease of the left long finger.
Fig. 3.44 Bowen’s disease. In patients with squamous cell carcinoma in
situ (Bowen’s disease) that is low risk, alternative therapies such as 5-
fluorouracil, imiquimod, photodynamic therapy, or vigorous cryother-
apy may be considered even though cure rate may be lower.
Fig. 3.45 Bowen’s disease of the posterior foot/ankle.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
69

skin cancer, male sex, significant smoking history, human papil-
loma virus (HPV), exposure to arsenic or hydrocarbons, pre-
vious radiation, and immunodeficiency.287
3.15.2 Ultraviolet Exposure
NMSCs are at least twice as frequent in men as in women,
hypothesized to be in part to greater environmental/UV expo-
sure. While cSCC has historically appeared in people over 50, a
bimodal pattern has recently emerged with more young people
aged 20 to 30 being diagnosed with the disease.31,53,54,288 The
number of women under age 40 diagnosed with SCC has espe-
cially increased in the last 30 years, and many experts attribute
this to their greater use of indoor tanning. More than 419,000
cases of skin cancer in the United States each year are linked to
indoor tanning, and over 70% of tanning salon patrons are
females.31,53,54,288 Frequent use of tanning beds also multiplies
the risk of SCC; people who use tanning beds are 2.5 times more
likely to develop SCC than those who do not.31,53,54,288
The majority of skin cancers in African-American, Latinos, or
other ethnicities with darker skin tones are cSCC, usually arising
on the sites of preexisting inflammatory skin conditions or burn
injuries.36,289 Though naturally dark-skinned people are less likely
than fair-skinned people to develop a cutaneous malignancy, it is
still essential to practice sun protection strategies. All skin types
are at risk of skin cancer. Recently, there has been a large increase
in new SCCs diagnosed in Latinos and other people of color.
Cumulative exposure to sunlight causes most cases of SCC.
3.15.3 Immunosuppression
Chronic immunosuppression resulting from either acquired
immunodeficiency syndrome or systemic drugs required for
most transplant recipients markedly increases the risk of cSCC
up to 250 times the general population and is closely correlated
to the type of transplant, immunosuppressive drug burden, and
the cumulative time since transplantation.282,283,284 The inci-
dence of SCC in transplant patients is much higher than that in
the general population: in Australia, 70% of transplant recipi-
ents develop SCC within 20 years of the transplant.290,291,292,293
Multiple reasons for this have been postulated. Genetics,
coupled with infection with HPV types 16, 18, and 31 and expo-
sure to UV radiation, may result in increased oncogenesis. In
addition, the use of prophylactic immunosuppressive agents in
patients who undergo transplant increases the risk for develop-
ing SCC. In transplant patients SCC tends to grow more rapidly,
metastasize more frequently, and results in higher mortality.294
These cancers are generally more aggressive, with an increased
risk of local and distant metastases.295,296,297,298 Heart trans-
plant recipients are at the highest risk of developing aggressive
or metastatic cSCC followed by renal, lung, and liver recipients.
Patients who su er from hematologic malignancies and myelo-
dysplastic syndromes are also at greater risk for developing
cSCC, with chronic lymphocytic leukemia and small lympho-
cytic lymphoma associated with the highest risk299,300,301
3.15.4 Inherited Disorders
Inherited skin conditions associated with a high risk for SCC
development include epidermolysis bullosa, xeroderma
Fig. 3.46 Human papillomavirus (HPV) induced squamous cell carci-
noma. The HPV, highly transmissible through sexual contact, has been
documented as a cause of one form of Bowen’s disease affecting the
genitals. HPVcan also arise in the mucous membranes of the nose and
mouth as well as on the skin. The Food and Drug Administration
approved an HPV vaccine for use by females aged 9 to 26 years in
2006, and one for males in the same age group in 2009. The vaccines
are considered highly effective in preventing HPVand thereby reducing
the risk of both genital warts and cervical cancer as well as Bowen’s
disease.
Fig. 3.47 Human papillomavirus induced squamous cell carcinoma
arising from the distal finger.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
70

pigmentosum, and epidermodysplasia verruciformis. Xero-
derma pigmentosum (XP), a rare autosomal recessive disease,
reduces the ability of the skin to repair damage to deoxyribonu-
cleic acid (DNA) caused by sun exposure. XP is caused by a defi-
ciency in DNA nucleotide excision or post-replication repair.
Individuals with this disorder develop severe skin damage with
minimal sun exposure. As a result, patients with XP have a ten-
dency to develop skin cancers at an early age. The median age
of onset of NMSCs in individuals with XP is 8 years.115 Patients
less than 20 years old have a >1,000-fold increased risk for
developing SCC.115,116,302 Albinism, a congenital defect in mela-
nin formation, is another example.303,304
3.15.5 Artificial Tanning
NMSCs are at least twice as frequent in men as in women,
hypothesized to be in part to greater environmental/UV expo-
sure. While cutaneous SCC has historically appeared in people
over 50, a bimodal pattern has recently emerged with more
young people aged 20 to 30 being diagnosed with the disease.
The number of women under age 40 diagnosed with SCC has
especially increased in the last 30 years, and many experts
attribute this to their greater use of indoor tanning.50,51,52,55,305
More than 419,000 cases of skin cancer in the United States
each year are linked to indoor tanning, and over 70% of tanning
salon patrons are females.50,51,52,55,305 Frequent use of tanning
beds also multiplies the risk of SCC; people who use tanning
beds are 2.5 times more likely to develop SCC than those who
do not.52
3.15.6 Chronic Inflammation
The majority of skin cancers in African-American, Latinos, or
other ethnicities with darker skin tones are cSCC, usually arising
on the sites of preexisting inflammatory skin conditions or burn
injuries. SCC arising from a chronic wound is also known as a
Marjolin’s ulcer,306 an occurrence that was first described by
Jean-Nicolas Marjolin in 1828. The most frequent site of occur-
rence is the lower extremity ( Fig. 3.48, Fig. 3.49).307,308,309,
310,311 Patients present with induration, elevation, ulceration,
and weeping at the site of a preexisting scar or ulcer. These
lesions have a high rate of metastases; one study reported that
32% of patients presenting with Marjolin’s ulcers had lymph
node metastasis at the time of diagnosis and distant metastasis
to the lungs, liver, bone, and brain accounted for 27% of cases.307
Marjolin’s ulcer behaves aggressively and has a propensity for
local recurrence and lymph node metastasis.312 While unable to
obtain distinct rates, the average period of latency cited is 35
years.313
3.15.7 Personal History of
Nonmelanoma Skin Cancer
A personal history of BCC or SCC is strongly associated with
subsequent SCC. A 2009 study from Ireland showed that indi-
viduals with a history of BCC had a 14% higher incidence of sub-
sequent SCC. This was particularly higher for men with a
history of BCC, with a subsequent SCC risk of 27% higher than
the general population.314 Also from this study, individuals with
melanoma were also 2.5 times more likely to report a subse-
quent SCC.314 There is an approximate 20% increased risk of a
subsequent lesion within the first year after a skin cancer has
been diagnosed. The mean age of occurrence for these NMSCs is
the middle of the sixth decade of life.14,315
Fig. 3.48 Marjolin’s ulcer. Areas of chronic wounds, trauma, and areas
of previous radiation or chemical exposure with chronic skin
inflammation can also give rise to squamous cell carcinoma. Marjolin’s
ulcers describe an aggressive type of squamous cell carcinoma that
develops in chronic wounds. These more often metastasize.
Fig. 3.49 Squamous cell carcinoma arising from chronic wound
(Marjolin’s ulcer).
Treatment of Squamous and Basal Cell Carcinoma of the Skin
71

3.15.8 Family History of Squamous Cell
Carcinoma or Associated Premalignant
Lesions
A family history of SCC may also increase the risk of SCC in first-
degree relatives. A recent review cites individuals with at least
first-degree relative a ected with SCC, in situ SCC, or AK had a
two to three times increased risk of invasive and in situ SCC rel-
ative to the general population.315,316 An increased number of
tumors in parents was proportionally associated with increased
risk to the o spring.315,316 Additional data from the population-
based data estimate genetic risk e ects of 8% and familial
shared-environmental e ects of 18%.317
3.16 Identification of High-Risk
Squamous Cell Carcinoma
Given the variability of cSCC behavior ( Fig. 3.50, Fig. 3.51,
Fig. 3.52), early identification of those cSCCs that are at high
risk for recurrence and metastasis is important, so that appro-
priate management can be initiated. Discussions attempting to
characterize high-risk features and their correlation with poor
outcomes have already been discussed in the beginning of this
chapter; however, no consensus exists regarding how to define
high-risk cSCC. The National Comprehensive Cancer Network
(NCCN) and the American Joint Committee on Cancer (AJCC)
have distinct criteria to determine whether a lesion is high risk.
Though di erent in perspective, both guidelines share the com-
mon goals of trying to identify “high-risk” cSCCs and improving
patient outcomes. Currently, no data supporting one definition
over the other have been validated. As a result, classification of
high-risk cancers remains with the clinician, taking into consid-
eration the patient, the history, and the characteristics of the
lesion.318
The purpose of the AJCC staging system is distinct from that
of the NCCN treatment guidelines.30,319 The goal of the AJCC
staging system is to stratify patients with similar outcomes into
groups to o er accurate prognostic estimates. AJCC staging is
almost entirely based on the “anatomic” characteristics of a pri-
mary tumor, using the tumor (T), node (N), and metastases (M)
classification.
In contrast to the AJCC staging system, which endeavors to
stratify patients of similar outcomes and provide prognostic
estimates, the NCCN guidelines are intended to direct tumor
treatment and management. Using the NCCN classification,
nearly 90% of the same cohort of tumors analyzed by the AJCC
staging system was deemed to be “high risk,” suggesting that
the NCCN’s definition of “high risk” cSCC may be too inclusive.
The NCCN and AJCC criteria to determine if a lesion is more
likely to demonstrate high-risk clinical behavior are presented
in Table 3.4 and Table 3.5, respectively.
Fig. 3.50 Squamous cell carcinoma. SCCs may occur on all areas of the
body including the mucous membranes and genitals, but are most
common in areas frequently exposed to the sun, such as the rim of the
ear, lower lip, face, balding scalp, neck, hands, arms, and legs.
Fig. 3.51 Squamous cell carcinoma arising from skin exhibiting chronic
ultraviolet exposure and damage. Surrounding skin in these areas
reveal clear signs of sun damage, including wrinkles, pigment changes,
freckles, “age spots,” loss of elasticity, and broken blood vessels.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
72

Fig. 3.52 Squamous cell carcinoma of the dorsal
right hand. Note erythematous granulation tissue
at the base of the ulceration.
Table 3.4 National Comprehensive Cancer Network (NCCN) criteria for
high-risk squamous cell carcinoma lesions
Low risk

High risk
Location/size

Area L<20 mm

Area L>20 mm
Area M<10 mm

Area M>10 mm
Area H<6 mm

Area H>6 mm
Borders

Well defined

Poorly defined
Primary versus recur-
rent
Primary

Recurrent
Immunosuppression

(–)

(+)
Site of prior radiation
therapy or chronic in-
flammation
(–)

(+)
Rapidly growing tumor (–)

(+)
Neurologic symptoms (–)

(+)
Degree of differentia-
tion
Well or moderately
differentiated
Poorly differentiated
Pathology subtype of
adenoid, adenosqua-
mous, desmoplastic
(–)

(+)
Depth of thickness

<2 mm

>2 mm
Perineural involvement (–)

(+)
Notes: Area H= “mask areas” of face (Fig. 3.32; central face, eyelids,
eyebrows, periorbital, nose, lips [cutaneous and vermilion], chin,
mandible, preauricular and postauricular, temple, ear), genitalia, hands,
and feet.
Area M= cheeks, forehead, scalp, neck, and pretibia.
Area L=trunk and extremities (excluding pretibia, hands, feet, nail units,
and ankles).
Table 3.5 American Joint Committee on Cancer (AJCC) criteria for high-
risk squamous cell carcinoma lesions and staging
Primary tumor (T)
TX

Primary tumor cannot be assessed
T0

No evidence of primary tumor
Tis

Carcinoma in situ
T1

Tumor 2 cm or less in greatest
dimension with less than two high-risk
features (see list of high-risk features
below)
T2

Tumor greater than 2 cm in greatest
dimension OR
Tumor any size with two or more
high-risk features
T3

Tumor with invasion of maxilla,
mandible, orbit, or temporal bone
T4

Tumor with invasion of skeleton (axial or
appendicular) or perineural invasion of
skull base
High-risk features for the primary tumor (T) staging
Depth/invasion

>2 mm thickness
Clark level≥IV
Perineural invasion
Anatomic location

Primary site ear
Primary site hair-bearing lip
Differentiation

Poorly differentiated or undifferentiated
Regional lymph nodes (N)
NX

Regional lymph nodes cannot be
assessed
Treatment of Squamous and Basal Cell Carcinoma of the Skin
73

The vast majority of SCCS cases are localized and require
minor surgical interventions, but in contrast to BCC, the biology
of SCCS can be more aggressive with a higher chance of local ex-
tension and/or metastasis. Tumors may manifest with in-transit
metastasis, satellitosis, discontinuous tumor growth pattern, and
extensive local infıltration or as local recurrences within flaps
and grafts near tumor beds that have been previously resected
or irradiated. The physician’s challenge lies in properly assessing
a patient’s risk for aggressive disease based on tumor or host
characteristics.
Generally accepted high-risk features include tumor diame-
ter >2 cm, poorly di erentiated histology, perineural invasion,
invasion beyond subcutaneous tissue/fat, occurrence on the ear,
temple, or anogenital regions, desmoplastic growth pattern,
and immunosuppressed host status.320,321 Like most malignan-
cies, the prognosis changes from excellent to poor once the
tumor has become locally advanced with regional lymph node
involvement and worse still with distant metastases. These
characteristics can guide decisions on surgical, radiation, and
medical management. However, it is unclear which factor or
combination of factors has the greatest prognostic signifıcance,
and the current AJCC staging system demonstrates limitations.
The di ıculty inherent in identifying high-risk SCCS was recog-
nized and addressed by the AJCC in 2010, with a revision of the
prior staging system that allowed SCCS to be staged separately
from other NMSCs and considers tumor location, depth, histol-
ogy, and perineural invasion. However, this revised system is
also not ideal for identifying high-risk SCCS, with the bulk of
poor outcomes occurring in stage T2 cases. Thus, an alternative
staging system to stratify T2 tumors based on the number of
four prognostic factors observed (poor di erentiation, perineu-
ral invasion, tumor diameter >2 cm, and invasion beyond
subcutaneous fat) was developed.322 Without widely available
prognostic information, high-risk lesions may be missed in
addition to wide variability in treatment.
3.16.1 Imaging
Routine imaging with computed tomography (CT), magnetic
resonance imaging (MRI), or positron emission tomography
(PET) for cutaneous SCC is not indicated, but may be obtained
based on clinical suspicion in patients that exhibit specific neu-
rological symptoms or regional lymphadenopathy.
3.17 Approach to Management
3.17.1 Topical Therapy
Since cure rates may be lower, superficial therapies should be
reserved for those patients where surgery or radiation is con-
traindicated or impractical.323 Superficial therapies include top-
ical treatment with 5-FU or imiquimod, photodynamic therapy
(PDT), and cryotherapy and were discussed previously in the
nonsurgical management of BCC.
3.17.2 Radiation Therapy
Given its noninvasive nature, radiation therapy (RT) has
been used as a nonsurgical prim ary treatment option for
high-risk cSCC. It has a wide range of cure rates, with
reported lower rates for aggressive cSCC types. RT has dem -
onstrated outcom es comparable to surgery for tum ors on
the lip and eyelid.324 It necessitates an intensive treatment
schedule involving weeks of comm itm ent and does not
allow for histologic confirm ation of tum or m argins. Addi-
tionally, there are side e ects of RT that som e patients m ay
not tolerate, including m alaise, nausea, induced erythema,
Table 3.5 continued
Primary tumor (T)
N0

No regional lymph node metastases
N1

Metastasis in a single ipsilateral lymph
node, 3 cm or less in greatest dimension
N2

Metastasis in a single ipsilateral lymph
node, more than 3 cm but not more
than 6 cm in greatest dimension; or in
multiple ipsilateral lymph nodes, none
more than 6 cm in greatest dimension;
or in bilateral or contralateral lymph
nodes, none more than 6 cm in greatest
dimension
N2a

Metastasis in a single ipsilateral lymph
node, more than 3 cm but not more
than 6 cm in greatest dimension
N2b

Metastasis in multiple ipsilateral lymph
nodes, none more than 6 cm in greatest
dimension
N2c

Metastasis in bilateral or contralateral
lymph nodes, none more than 6 cm in
greatest dimension
N3

Metastasis in a lymph node, more than
6 cm in greatest dimension
Distant metastasis (M)
M0

No distant metastases
MI

Distant metastases
Anatomic stage/prognostic groups
Stage 0

Tis

N0

M0
Stage I

T1

N0

M0
Stage II

T2

N0

M0
Stage III

T3

N0

M0
T1

N1

M0
T2

N1

M0
T3

N1

M0
Stage IV

T1

N2

M0
T2

N2

M0
T3

N2

M0
Any T

N3

M0
T4

Any N

M0
Any T

Any N

M1
Treatment of Squamous and Basal Cell Carcinoma of the Skin
74

telangiectasia, or hypopigm entation, epiderm al atrophy, soft-
tissue necrosis, and radiation-induced m alignancy.324 There-
fore, RT is often best suited for patients who are poor surgi-
cal candidates, have tum ors in inoperable locations, or
whose reconstruction would cause cosm etic or functional
deficits325 Additionally, RT is used most frequently as salvage
or palliative therapy in tum ors that have failed to respond to
other treatm ent options.318,326
RT may also be used judiciously for treatment of positive
margins upon excision. Typical clinical indications for postope-
rative RT include large tumor size, rapid growth, recurrent dis-
ease, and neurological compromise at presentation. Typical
pathologic indications for postoperative RT include grossly pos-
itive margins, extensive perineural invasion, bone invasion, and
the presence of risk factors such as satellitosis and poorly di er-
entiated histology.30 Adjuvant radiotherapy is also usually rec-
ommended for patients with parotid-area node metastases as
well as to involved nodal regions within the axilla and groin
because the risk of nodal relapse is high with surgery alone.327
3.17.3 Surgical Management
Localized SCC is most commonly treated with surgery. In an
evidence-based review of the literature, the best results were
obtained with surgery.179 However, consideration of function,
cosmetic outcome, and patient preference may lead to the
choice of other therapy as primary treatment in order to
achieve optimal overall results.328
Although many low-risk squamous cell cancers are managed
by dermatologists and primary care physicians with methods
such as cryotherapy or electrodesiccation and curettage, this
approach does not permit histologic confirmation of clear mar-
gins and is generally contraindicated for recurrent, large, poorly
defıned, and other high-risk tumors as well as tumors that
invade into or beyond the subcutaneous fat. In these instances,
conventional surgical excision (SE) with postoperative margin
assessment (POMA), consisting of standard SE followed by post-
operative pathologic evaluation of margins should be consid-
ered. This technique has been reported to achieve 5-year
disease-free rates of over 98% for BCC and 92% for SCC.228 The
downside of this approach is that the specimen’s histological
margins are evaluated by a bread-loafing technique that,
although allows great visualization of the tumor and surgical
margins of the studied section, does o er only a sample evalua-
tion of the real surgical margin.
If low-risk lesions can be excised with the recommended
margins, then either linear closure or secondary intention heal-
ing are appropriate reconstructive approaches. However, if tis-
sue rearrangement or skin graft placement is necessary to close
the defect, intraoperative surgical margin assessment should be
performed before closure.
Excision with comprehensive intraoperative margin control
is in our opinion the preferred surgical technique for high-risk
BCC and SCC. These include either excision with CCPDMA with
frozen section or Mohs micrographic technique. However, if
standard excision with POMA is used for treatment of a high-
risk tumor due to patient-related clinical circumstances or
other variables, wider surgical margins than those recom-
mended for low-risk lesions must be taken and increased recur-
rence rates should be expected.241
Based on the published work of Zitelli and colleagues, low-
risk tumors defined by size smaller than or equal to 2 cm, well
or moderately di erentiated, thinner than 2 mm, and located
on trunk or extremities, can be safely resected with 4-mm mar-
gins. Tumors with any of the described high-risk features war-
rant 6-mm margins or more.329 It is important to remember
that any peripheral rim of erythema around an SCC must be
included in what is assumed to be the tumor.
Based on numerous reports with low level of evidence, Mohs
micrographic surgery (MMS) is considered by dermatologists as
standard of care for SCCs because of the reported highest cure
rates and the ability to intraoperatively analyze 100% of the
excision margin. An important and equivalent alternative to
MMS is an excision with complete circumferential peripheral
and deep margin assessment (CCPDMA), either with frozen or
permanent section. However, this alternative requires the sur-
geon and dermatopathologist (Fig. 3.30) to work closely
together in order to achieve the same cure rate that can be
obtained using the Mohs technique (Fig. 3.53).
For most cutaneous basal cell carcinomas (BCCs) and squa-
mous cell carcinomas (SCCs), data are insu cient to permit evi-
dence-based choices among treatments. A broad review
published in 2014 in the Cochrane Database of Systematic
Review aimed to compare MMS versus SE for periocular basal
cell carcinoma BCC based on the e ectiveness, cost, complica-
tions, and acceptability of the techniques.330 The selection crite-
ria planned to include only randomized controlled trials (RCTs)
comparing SE with MMS in order to bring the highest level of
evidence. The authors were unable to find any studies that
m et the inclusion criteria for this review and hence none
were included for analysis. Since only low level of evidence
of nonrandom ized studies describing the techniques are
reported, no reliable conclusions could be reached regarding
which m ethod of treatm ent (SE or MMS) resulted in a lower
recurrence or complication rate for periocular BCC. No stud-
ies were found comparing the cost of either method directly.
The authors concluded that high-quality RCTs are therefore
needed to improve the evidence base for the m anagem ent of
this condition.330
To compare tumor recurrence after treatments, a prospective
cohort study of consecutive patients with primary NMSCs
treated with the most common treatments was conducted in
two practices in 1999–2000. Recurrence was determined from
medical records by observers blinded to treatment type. Fol-
low-up was available for 1,174 patients with 1,488 tumors
(93.8%) at median 7.4 years; of these tumors, 24.3% (N1⁄ 4,361)
were treated with destruction with electrodessication/curet-
tage, 38.3% (N1⁄ 4,571) with excision, and 37.4% (N1⁄ 4,556)
with histologically guided serial excision (Mohs surgery). The
overall 5-year tumor recurrence rate (95% confidence interval)
was 3.3% (2.3, 4.4). Unadjusted recurrence rates did not di er
after treatments: 4.9% (2.3, 7.4) after destruction, 3.5% (1.8, 5.2)
after excision, and 2.1% (0.6, 3.5) after Mohs surgery (P1⁄ 4,
0.26), and no di erence was seen after adjustment for risk fac-
tors. In tumors treated only with excision or Mohs surgery, the
hazard of recurrence was not significantly di erent, even after
adjustment for propensity for treatment with Mohs surgery.
These data indicate that common treatments for NMSCs were at
least 95% e ective, and further studies were needed to guide
therapeutic choices for di erent clinical subgroups.331
Treatment of Squamous and Basal Cell Carcinoma of the Skin
75

The only other randomized prospective clinical trial pub-
lished in 2014 has been used by the dermatology community to
justify the use of MMS over conventional SE.332 This is the first
prospective randomized study that compares SE and MMS for
treatment of high-risk primary BCC (pBCC) and recurrent facial
BCC (rBCC) with a long-term follow-up. In this 10-year follow-
up study, 408 patients with BCCs in 374 patients were ran-
domly assigned to treatment with SE or MMS. The authors
found that for primary BCC, the 10-year cumulative probabil-
ities of recurrence were 4.4% after MMS and 12.2% after SE
(Log-rank test v2 2.704, p =0.100). For recurrent BCC, cumula-
tive 10-year recurrence probabilities were 3.9% and 13.5% for
MMS and SE, respectively (Log-rank v2 5.166, p =0.023). A sub-
stantial proportion of recurrences occurred after more than
5 years after treatment: 56% for pBCC and 14% for rBCC. The
author’s conclusion was that fewer recurrences occurred after
treatment of high-risk facial BCC with MMS compared to treat-
ment with SE.332 Among several biases and limitations in this
study, we want to point out three that a surgeon should be
aware of before accepting the authors’ conclusions: (1) 62% of
the study subjects were lost during follow-up. For these
patients, the follow-up was probably truncated at the last
known clinic visit. An assumption for the validity of the
Kaplan–Meier survival analysis, used to estimate the recurrence
rates, is that losses to follow-up are unrelated to the endpoint.
Thus, the question of whether patients who were lost to follow-
up were more or less likely to return or not to return to the
clinic because their tumor was recurring. It is possible that
these patients had a recurrence and chose to seek treatment
elsewhere and may indeed be plausible that a patient who
would regard a recurrence as a treatment failure would seek
another clinic. Such scenarios would violate this strong assump-
tion of the Kaplan–Meier analysis and would bias the
estimate.333 (2) Margins of 3 mm were used in this study
although margins of 4 to 5 mm for these high-risk primary and
recurrent facial BCCs are typically advised. The large number of
incomplete excisions (18% of pBCC and 32% of rBCC assigned to
SE were incompletely removed after the first excision) confirms
that a surgical margin of 3 mm is not su cient in these high-
risk BCCs.334 (3) The SE had the histological margins evaluated
by a bread-loafing technique and not by CCPDMA. Since bread-
loafing technique o ers only a sample evaluation of the real
surgical margin (approximately 1–2%) and MMS 100%, the only
conclusion that can be made is that MMS is superior to bread-
loafing technique for histological margins assessment but not
to the SE itself.
The Mohs micrographic surgical procedure is an important
modality that achieves high cure rate for most common skin
cancers using an intraoperative stepwise histologic evaluation
of surgical margins, but the success of the procedure is inher-
ently tied to the reliability of each of many steps that make up
the technique. Pitfalls in histologic preparation of the tissue
specimens may occur during debulking, excising, orienting, cre-
ating the map, sectioning, inking, tissue flattening and freezing,
cutting, slide fixation, staining, and mapping the tumor. Chal-
lenges are also present in the interpretation of the slides.335
A critical component of Mohs technique is the dermatolo-
gist’s skill in interpreting histologic specimens. Fellowship-
trained Mohs surgeons spend much of their time at the micro-
scope acquiring dermatopathology expertise, which improves
steadily in relation to the number of cases. A recent study
showed more than 1,300 Mohs surgery cases and more than
6 months of fellowship training were required before reducing
errors to a minimum acceptable level of less than 1 critical error
per 100 cases read.336 Frozen section slides may be more di -
cult to interpret than formalin-fixed permanent sections, and
most dermatologists and pathologists have no experience in
examining horizontally cut sections. The Mohs surgeon must
follow a systematic, comprehensive, and reproducible system
for evaluation of the frozen section slides, correlating the find-
ings observed with the three-dimensional specimen repre-
sented by sequential cuts.336
Fig. 3.53 Squamous cell carcinoma (SCC). A persistent, scaly, elevated red patch with irregular borders. These lesions often crust or bleed. Staged
excision of an SCC with use of irradiated human skin allograft. (a) Intraoperative placement of IHSA. (b) One week postoperative appearance of the
allograft. (c) Intraoperative removal of the dried allograft after clear margins. (d) Fresh wound bed revealed underneath allograft.
Treatment of Squamous and Basal Cell Carcinoma of the Skin
76

There are many challenging situations in which Mohs sur-
geons must be able to decide whether what they see is a malig-
nant process or a benign structure such as an adnexal structure.
Inflammatory cells can be mistaken for both a malignant proc-
ess and obscure malignant cells. Inflammation can also obscure
or resemble SCC. Using immunohistochemistry, Zachary and
colleagues documented single cells or small clumps of SCC in
areas that had been deemed clear (inflammation only) by H&E
staining.337
The concept created by the general surgeon Frederic Mohs is
at the same time creative and e cient, assuring complete surgi-
cal margin examination while conserving the maximum
amount of normal tissue based on the concept of contiguous
spread of a tumor from a single focus. The low acceptance of
MMS in Europe and other countries may be related to particu-
larities of their health care systems; due to the higher costs and
the tedious, time-consuming nature of the procedure; inability
to remove a large or di cult tumor in 1 day precluding imme-
diate reconstruction after complete excision and the need of a
specially trained dermatologist and ancillary personnel not
available in the majority of the countries.
In cases of locally advanced and metastatic SCCs of the head
and neck that clearly involve lymph nodes, surgery and adju-
vant RT have generally been considered best practice and the
best chance for achieving locoregional control.327 The evalua-
tion of subclinical metastases in the nodes, however, is not yet
standardized. The presence of cervical lymph node metastases
carries the most prognostic weight in terms of rates of recur-
rence and overall survival for cutaneous SCC of the head and
neck. Thus, early identification of nodal disease is essential as it
a ects decisions regarding lymphadenectomy and adjuvant
radiation. When there is histologic confirmation of lymph node
involvement, the preferred treatment is regional lymph node
dissection.338
Controversy remains in the management of high-risk cutane-
ous SCC with no clinical or radiological evidence of metastatic
disease (clinical N0 disease). Elective lymphadenectomy is not
advocated given its high morbidity compared to the benefit of
the procedure.339,340 The utility of sentinel lymph node biopsy
(SLNB), a common practice in melanoma, is not clearly defined
in the setting of SCCs. For certain high-risk cutaneous SCC, SLNB
may be considered. A systematic review of 692 patients with
cutaneous SCC reported positive sentinel lymph nodes in 24
and 21% of anogenital and nonanogenital patients, respec-
tively.341 However, the survival benefits of the SLNB remain
unclear.
Criteria that have been proposed for consideration of SLNB in
cutaneous SCC include size >2 cm, clinical evidence of deep
invasion (>8 mm), immunosuppression, development in a scar
from burn or trauma, high-grade pathologic features such as
perineural, lymphatic, or vascular di erentiation or poor di er-
entiation, and locations such as the ear, nasal vestibule, or
lip.342 When two or more high-risk features are present, the
rate of lymph node metastases (assessed by an SLNB) has been
cited as 29.4%.321 This number rises to 50% when four risk fac-
tors are present.343
In a recent systematic review, the authors successfully dem-
onstrated the feasibility and reliability of SLNB for accurate
staging of head and neck SCCS patients with a false omission
rate of only 4.76%, similar to the experience with melanoma.344
SLNB use may improve survival rates in SCCS, not only by iden-
tifying subclinical lymph node involvement, but also by locating
the correct draining nodal basin, which would guide directed
therapy at an earlier and potentially more curable point of
regional metastatic spread. In comparison to melanoma, there
may be more potential for control of metastatic spread in SCCS
considering the propensity to metastasize predominantly to
regional lymph nodes and the overall radiosensitivity of the
disease. SLNB may prove most beneficial in identifying patients
within the high-risk SCCS group that would likely progress to
develop locoregional disease.
3.17.4 Additional Treatment Modalities
Systemic treatments in the adjuvant, neoadjuvant, or metastatic
disease settings are not well studied. Extrapolations for cutane-
ous SCC therapy have been made, with varying degrees of suc-
cess, from regimens utilized in head and neck SSCs; however,
there is lack of information from prospective trials to formulate
specifıc guidelines. Active agents usually include platinum com-
pounds, 5-fluorouracil (5-FU), or biologic response modifıers
such as interferon–alpha or retinoic acids. With respect to adju-
vant therapy, based on studies of mucosal SCC, NCCN guidelines
indicate that chemo-RT with cisplatin could be considered in
select patients, particularly if extracapsular extension and
microscopic invasion of margins are noted.30
In the locally advanced or metastatic setting, patients with
advanced cutaneous SCC have historically been treated with
platinum-based chemotherapy regimens.345,346,347,348,349
A
major limitation of these studies is the heterogeneity of the
populations reported, with both locally advanced and meta-
static patients undergoing therapy with or without concomi-
tant RT often reported within the same study, a confounding
factor since patients with locally advanced disease often have a
better prognosis.347 The presence of many anecdotal case
reports and few randomized studies can be confusing. With
regard to larger phase II trials, all studies are small and
nonrandomized.
Investigation of targeted therapies such as epidermal growth
factor receptor (EGFR) inhibitors with radiation is also currently
ongoing.350 A phase II trial is currently under way to evaluate
the e ıcacy of this potential regimen. Future studies exploring
targeted therapy and/or chemotherapy and RT in this space are
necessary to advance treatment standards. In recent years, the
approval of cetuximab, a monoclonal antibody that inhibits the
activity of the EGFR receptor, has opened another possible
avenue for systemic treatment of patients with advanced cuta-
neous SCC. Cetuximab has shown activity in squamous carcino-
mas of the head and neck and has also shown activity in SCCS
in a small number of publications.350 However, it is important
to note that although impressive responses have been seen with
cetuximab, the majority of patients who receive this therapy do
not respond, suggesting that clinical trials to determine which
patients may be most likely to respond and if combination
strategies may produce superior outcomes are warranted.
Advances in the development of immune checkpoint inhibi-
tors that blockade the programmed death protein 1 (PD-1) and
programmed death ligand 1 (PDL-1) have demonstrated intrigu-
ing responses in advanced melanoma and squamous tumors of
the lung.351 An additional report of preclinical cutaneous SCC
Treatment of Squamous and Basal Cell Carcinoma of the Skin
77

animal models demonstrated that immune neutralization of PD-
1 cells resulted in decreased papilloma incidence that was asso-
ciated with CD4 and CD8 T-cell infıltrates, as well as increased
interferon and decreased transforming growth factor production
within tumors, supporting the role of PD-1 blockade in cutane-
ous SCC.352 As more trials are created to evaluate the role of
novel immunotherapeutics in solid tumors, their use alone and
possibly in combinatorial therapy with EGFR blockade is a
rational consideration in the treatment of cutaneous SCC.
3.17.5 Long-Term Management and
Follow-Up
The most current recommendations for follow-up of patients
with high-risk cutaneous SCC are detailed below, although no
absolute guidelines have been established. Ultimately, long-
term follow-up and management relies on the expertise of the
clinician.353 Patients with high-risk cutaneous SCC have a
greater risk of developing recurrence, lymph node or distant
metastasis, or another high-risk tumor.354 Of these high-risk
lesions, 70 to 80% will locally recur or metastasize within the
first 2 years and 95% within the first 5 years of the initial cuta-
neous SCC diagnosis.355 Additionally, between 30 and 50% of
patients will develop a second skin cancer within 5 years.356
Close clinical follow-up is, therefore, essential. Generally,
patients treated for high-risk lesions should be examined every
3 to 6 months for the first 2 years, then yearly thereafter. A full
skin examination, palpation of regional lymph nodes, and eval-
uation for neurologic symptoms should be performed at every
follow-up visit. A multidisciplinary team approach involving
cutaneous, medical and radiation oncologists, oncologic sur-
geons, and dermatopathologists should be considered for very
high-risk patients to optimize follow-up and disease-free
survival.
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Treatment of Squamous and Basal Cell Carcinoma of the Skin
85

4 Surgical Treatment of Cutaneous Melanoma
Andrea M. Abbott, Matthew P. Doepker, and Vernon K. Sondak
4.1 Epidemiology
Melanoma is currently the fifth most common cancer in the
United States, and its incidence is continuing to increase. In
2017, over 87,000 new cases of invasive melanoma will be diag-
nosed, accounting for about 4.5% of new cancer cases in the
United States. Although the 5-year survival rate continues to
improve, and is now estimated at 92% for all stages at presenta-
tion, about 10,000 deaths from this disease now occur in the
United States annually.1 Because of its relatively early age of
onset, melanoma is one of the most devastating malignant dis-
eases in terms of the years of potential life lost per death.2
Both environmental and genetic factors increase an individu-
al’s risk for developing melanoma (Table 4.1). Caucasian race
and fair complexion predispose an individual to developing
melanoma, as do mutations in several known—and likely multi-
ple as yet unknown—melanoma susceptibility genes.3,4 Mela-
noma a ects a broad age range. According to recent cancer
statistics, the peak incidence is between the ages of 55 and 74
years, with a median age at time of diagnosis of 64 years.5
Three-quarters of all cases will occur before age 70, and approx-
imately 20% occur in individuals under 40 years of age. Environ-
mental exposure in the form of ultraviolent radiation is
the most well-studied and modifiable etiologic factor in the
development of melanoma. Intermittent, high-intensity expo-
sure (e.g., blistering sunburns) contributes most dramatically to
the development of melanoma. Dark-skinned individuals may
be less likely than fair-skinned individuals to develop mela-
noma due to the protective e ect of eumelanin. Even in individ-
uals with a genetic predisposition, exposure to ultraviolet
radiation is the primary factor determining whether an at-risk
person actually develops melanoma.6,7
4.2 Biopsy Techniques and
Orientation of Incision
Any patient who presents with a new or abnormal pigmented
skin lesion, with increasing size, change in color, or developing
irregular borders, should be considered for a biopsy for defini-
tive diagnosis. The approach to biopsy for a suspicious cutane-
ous lesion often varies depending on the location of the lesion
and the preference and training of the physician performing the
biopsy. The gold standard for tissue diagnosis when melanoma
is suspected is excisional biopsy with a 1 mm to 2 mm margin
of normal skin, including some subcutaneous fat (see Chapter
2). This may not be feasible in all cases due to the location of
the lesion, and often is more than the minimum necessary for
the diagnosis of a benign lesion.8
Several other biopsy
approaches are reasonable to achieve adequate tissue to allow
the pathologist to make a diagnosis and assess all relevant his-
tologic features. These techniques include superficial shave
biopsy, deep scallop shave biopsy, punch biopsy, incisional
biopsy, and the aforementioned excisional biopsy. When any
form of partial biopsy is performed, the biopsy should focus on
obtaining a sample of the most elevated portion of the lesion to
provide the best estimate of tumor thickness. It is ideal to also
include a portion of normal skin in the biopsy; however, the
main goal should be to obtain the most suspicious and elevated
portion of the lesion in the specimen. For lesions that are large
or in cosmetically sensitive areas, a punch biopsy that obtains
a full-thickness sample is often the best initial diagnostic
approach. If a partial biopsy is performed and a portion of the
suspicious lesion remains, indicating this on the pathology
request helps make the pathologist aware that the lesion was
not removed in its entirety, aiding in the diagnostic process.
If a lesion is suspected to be melanoma, cryosurgery and elec-
trodessication should not be performed given they can distort
normal tissue planes and do not allow for an adequate histo-
logic evaluation. Partial-thickness shave biopsy of pigmented
lesions remains controversial. One of the biggest criticisms
of shave biopsy is that partial sampling does not assess the
true thickness of a melanoma, if present. Thus, inaccurate
Table 4.1 Risk factors influencing the development of cutaneous mela-
noma
Demographic risk factors
Race

Caucasian >Hispanic >American
Indian/Alaska Native >Asian Pacific
Islander >Black
Gender

Male >Female
Age

Median age at diagnosis 62 years
old
Phenotypic features

Light hair, light eyes, fair skin,
multiple atypical nevi
Environmental risk factors
Ultraviolet light

Intermittent/intense and chronic
cumulative exposure
Cancer history

Melanoma or nonmelanoma skin
cancer: threefold relative risk
Childhood history of sarcoma,
lymphoma, leukemia, or central
nervous system: 2.5-fold risk
Immunosuppression

Threefold to fourfold risk after
organ transplantation
Socioeconomic status

More likely to have thicker and
more aggressive tumors if lower
socioeconomic status
Genetic risk factors
Family history of melanoma

1.7-fold increased relative risk
CDKN2A, CDK4 mutations

Familial melanoma syndrome
Source: Adapted from Sondak VK, Jensen EJ, Margolin KA. Melanoma
and other cutaneous malignancies. In: Norton JA, Barie PS, Bollinger RR,
et al, eds. 2nd ed. Surgery: Basic Science and Clinical Evidence. York, NY:
Springer; 2008.
Surgical Treatment of Cutaneous Melanoma
86