Skin Tumors I: Nonmelanoma Skin Tumors

Ross IS Zbar MD and Willis I Cottel MD

INTRODUCTION nally manipulated. Fitzpatrick5 classifies skin into six

Nonmelanoma skin cancers are the most com-
mon cancers of Americans, comprising fully 50%
of all the cancers diagnosed every year.1,2 Clini-
cally these tumors range from erythematous, tan
or off-white plaques, to smooth or ulcerative pap-
ules, nodules, subcutaneous nodules, or deep
ulcerations. Their biologic behavior is also quite
variable, some following a relatively benign course
and others progressing to extreme morbidity, muti-
lation, metastasis, and death.
types according to melanin content, inherent pig-
mentation, and sensitivity to UV light (Table 1).
The lower the Fitzpatrick type, the less melanin
pigment within the skin.
TABLE 1
Fitzpatrick’s Classification of Sun-Reactive Skin Types

RISK FACTORS IN SKIN CARCINOGENESIS

The etiology of skin cancer is multifactorial, but
risk factors can be broadly categorized as host-
related or environmental. Host factors that predis-
pose an individual to nonmelanoma skin cancer
include phenotype, genetic syndromes, precursor
lesions, and immunologic variables. Environmental
factors include exposure to ultraviolet (UV) radia-
tion, ionizing radiation, and chemicals.3

Host Factors
Phenotype. Actinic damage is recognized as a
major factor in the development of skin cancer.
Sun-exposed skin represents the main site of basal
and squamous cell carcinoma.4 The ability to tan is
one of the most important defenses of the skin
against nonmelanoma skin cancer. Tanning ability
is directly related to the amount of melanin in a
person’s skin, which in turn determines photosen-
sitivity. The damaging effects of UV radiation are
attenuated through both reflection/refraction by
the stratum corneum and through direct UV radia-
tion absorption by the melanin pigment. Tanning is
the body’s protective response to UV rays: Radia-
tion damage is ameliorated by increasing melanin
production and hence UV absorption by pigment.
The number of melanin-producing cells in the
skin is genetically determined and cannot be exter-
(Data from Fitzpatrick TB: The validity and practicality of sun-
reactive skin types I through VI. Arch Dermatol 124:869, 1988.)
Glogau6 recognizes four grades of actinic dam-
age to the skin (Table 2).
Photosensitivity—and the ability to tan—play key
roles in the development of skin cancer. Scandina-
vians with fair skin but good tanning ability have a
lower incidence of basal cell carcinoma than fair-
skinned Irish who tan poorly.7 Susceptibility to skin
tumors is inversely related to the content of mela-
nin in the skin and the ability to form a protective
tan.8 Skin phenotype, therefore, is an important
risk factor in the development of nonmelanoma
skin cancer.
SRPS Volume 9, Number 5
TABLE 2
Glogau’s Classification of Photoaging Groups
(Adapted from Glogau RG: Presentation at the Chemical Peel
Symposium, American Academy of Dermatology, Atlanta, De-
cember 4, 1990.)
The pattern of sun exposure is also important.
Overall, squamous cell carcinoma is associated with
the number of lifetime sunburns.9 Persons who
are exposed to UV radiation at irregular intervals
(eg, vacations, weekends) are at higher risk of
developing basal cell carcinoma than those who
are exposed regularly.10 In addition, sun exposure
during childhood and adolescence will predispose
the adult to skin cancer.11
Syndromes. Genetic disorders that decrease
protection against sun exposure consequently
increase the risk of nonmelanoma skin cancer.
Xeroderma pigmentosum is a rare hereditary
disorder characterized by intolerance of the skin
and eyes to ultraviolet radiation. XP is an autoso-
mal recessive condition due to defects in the DNA
repair mechanism of UV-induced damage. 12
Hypersensitivity manifests early in life as persis-
tent erythema, pigmentation, freckling, photopho-
bia, premature aging of skin, and multiple epithe-
lial neoplasms. Because tumors are multiple and
extensive, most patients succumb to the disease
early in life. Treatment involves sun avoidance
and sun protection.
2
Nevoid basal cell syndrome (Gorlin’s syndrome)
is characterized by multiple basal cell carcinomas
scattered throughout the body; cysts of the jaws
(odontogenic keratocysts); bifid ribs; scoliosis;
brachymetacarpalism; overdeveloped supraorbital
ridges; broad nasal root; hypertelorism; palmar and
plantar pits; and calcification of the falx cerebri.
The disorder is autosomal dominant.13,14 Recent
genetic analysis has located this disease to the long
arm of chromosome 9 at the locus of a tumor
suppressor gene.15
Albinism, an autosomal recessive disorder, is
characterized by absence of melanin. Affected
persons are at increased risk of developing skin
cancer, particularly squamous cell carcinoma.
Epidermodysplasia verruciformis is characterized
by wart-like, lichenoid, flat-topped lesions. This dis-
ease is partially of viral etiology and partially inher-
ited as an autosomal recessive inability to resist
infection by human papillomavirus types 3 and 5 in
sun-exposed regions. These lesions can degener-
ate into epithelial cell carcinoma.
Porokeratosis is an autosomal dominant skin dis-
order involving abnormal keratinization and occa-
sional malignant degeneration to squamous cell
carcinoma.16 The lesions are characterized by dis-
seminated annular plaques with sharply raised horny
borders. The lesions may be solitary or number in
the hundreds. Treatment with radiation therapy
promotes malignant change. Approximately 13%
of porokeratosis lesions will convert to a malignant
skin tumor.15
Predisposing Lesions. Several congenital or
acquired lesions may predispose a person to
develop skin cancer.
The nevus sebaceous of Jadassohn is present at
birth on the scalp or face and stays fairly quiescent
throughout childhood. Typically the lesion is well
circumscribed, slightly raised, hairless, and presents
a yellowish plaque that often becomes verrucous,
nodular, and much more noticeable at puberty.
The condition is not associated with any systemic
disease. Approximately 10% undergo malignant
degeneration to basal cell carcinoma.

Actinic keratoses (AK) are the most common
precancerous skin lesions of the epidermis. They
are also known as solar keratoses or senile kera-
toses. AK result from chronic sun exposure and
resultant skin damage, thereby serving as a marker
of solar damage. Untreated they can remit, remain
stable, or progress to squamous cell carcinoma. A
5-year study by Marks and associates17,18 found a
10% risk of malignant transformation of actinic kera-
toses to squamous cell carcinoma. Another study
by Graham19 calculated a 13% transformation rate.
AK occur as macules or papules with scaly,
irregular surfaces that are rough to the touch. In
contrast, seborrheic keratoses, benign lesions with-
out malignant potential, are waxy and greasy-feel-
ing. AK range in size from a few millimeters to
several centimeters. There may be one or two
lesions or many, but all occur in regions of sun
exposure. Their color ranges from skin tones to
reddish brown or yellow. Biopsies must be per-
formed of larger lesions, lesions with erosion, or
lesions refractory to treatment to rule out malig-
nant transformation.
Because AK have malignant potential, treatment
is essential.20 The American Academy of Derma-
tology recommends that actinic keratoses be
treated to prevent conversion to squamous cell
carcinoma. Treatment of these premalignant lesions
avoids the potentially more invasive and extensive
treatment of subsequent malignancy.21 Treatment
of AK achieves several goals: elimination of poten-
tial cancer risk; rejuvenation of the skin with eradi-
cation of the lesions; and elimination of the itching
and burning associated with AK. Appropriate treat-
ment can be by laser, chemical peel, cryotherapy,
curettage, tangential excision, or 5-fluorouracil (5-
FU).
Therapies that rely on skin destruction to cure
multiple AK can leave the patient with severely
hypopigmented or scarred skin. Only 5-FU can
adequately treat large regions of AK without leav-
ing scar. Indications for 5-FU include patients with
previous skin cancers and patients with large regions
of multiple AK. Treatment with 5-FU is not easy:
The patient must rub either the 1% or 5% topical
medication on the AK twice daily for 2–3 weeks.
Bedtime application is to be avoided so as not to
smear the medicine on the bedsheets. After 1
week, the treated area becomes red and raw. Treat-
ment should last until there is a vigorous inflamma-
SRPS Volume 9, Number 5
tory response and erosion occurs. Healing begins
after treatment with 5-FU ceases.
Cutaneous horns are hard, keratotic growths
reminiscent of a miniature animal horn that pro-
trude from relatively normal-looking skin. The domi-
nant feature is a keratotic mass that is as long or
longer than it is wide.22 Histologically the lesions
are essentially very advanced actinic keratoses.
Superficial removal is adequate treatment when
the process does not infiltrate the subdermal tis-
sues. A more thorough resection is indicated in
the presence of tumor extension, as approximately
10% of cutaneous horns have an underlying squa-
mous cell carcinoma.23
Immunologic Factors. Chronically sun-exposed
skin is known to have altered immune responsive-
ness and a statistical predisposition to skin cancer.24
Cell-mediated immunity is very likely a major host
defense mechanism against invasion by basal and
squamous cell carcinomas25 and is one of the fac-
tors accounting for the different growth rates of
these tumors. Large, deeply invasive tumors are
associated with low T-cell levels and absent lym-
phocytic infiltration at the tumor margins. In con-
trast, small, localized tumors are associated with
near-normal T-cell levels and adequate or increased
lymphocytic infiltration.
Two basic immunologic defense mechanisms
prevent tumor growth progression: natural killer
(NK) cells and T cells. Habets and others26,27 and
Kohchiyama and colleagues 28,29 have shown
abnormal natural killer cell activity in basal and squa-
mous cell carcinomas. Helper T cells are known to
play a central role in mediating the activity of natu-
ral killer cells. Studies of the inflammatory infiltrate
around skin tumors show that it consists mainly of
T cells and the T helper subset predominates over
the T suppressor/cytotoxic subset. This observa-
tion led Habets27 to the conclusion that the immune
response to the presence of a skin cancer is prima-
rily T cell-mediated and that T cells play a major role
in the body’s defense against the proliferation of
basal cell carcinoma.27
By producing interferon and interleukin-2, helper
T cells stimulate natural killer cell cytotoxicity that
plays a crucial role in tumor rejection. In addition,
Halliday and coworkers30 suggest that “spontane-
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SRPS Volume 9, Number 5

ous regression of human skin tumors is likely to be for DNA repair from solar damage break down
immunologically mediated, and that CD4+ T lym- with advancing age, the rate of skin cancer
phocytes seem to mediate this regression.” increases.
Kim and associates31 demonstrated production UV radiation-induced mutations in the p53 tumor
of type 2 cytokines, IL-4 and IL-10, by cutaneous suppressor gene have been frequently identified in
basal and squamous cell carcinomas. Cytokines human skin cancers.39-46 The p53 gene regulates
play a vital role in the host immune response by the cell cycle, and inhibition of the p53 gene prod-
regulating the development and function of immu- uct appears to play a significant role in the develop-
nocompetent cells. The authors propose that tumor ment of many cutaneous carcinomas.46 Nelson et
production of IL-10 may provide a mechanism for
al40 found p53 mutation in 92% of squamous cell
evading the local T cell-mediated immune response.
carcinomas and in 80% of actinic keratoses. In
The capacity of tumors to locally inhibit host contrast, normal skin samples were negative for
immunity may be a function of the aggressive nature
p53 mutations.
of the tumor rather than its occurrence in a privi-
leged anatomic site, as previously supposed.32 Urano and colleagues43 evaluated p53 mutations
Soluble extracts of highly aggressive BCC from in the skin surrounding basal cell carcinoma. The
sites prone to recurrence are capable of inhibiting authors conclude that “ultraviolet light irradiating
in vitro lymphocytic response,33 while localized the skin in daily life induces p53 accumulation in
tumors from less risky sites do not. the epidermis and secondly that the frequent clonal
Laboratory animals that have been exposed to expansion of p53 mutant cells occurs in the epider-
UV radiation in subcarcinogenic doses for a long mis adjacent to BCCs.”
time are more susceptible to transplantation of highly
antigenic, UV-induced cancers, suggesting a sys-
Environmental Factors
temic effect on suppressor T cells for specific UV-
induced tumor antigens.34 Kripke35 theorizes that Ultraviolet Radiation. The electromagnetic
exposing human skin to UV radiation has systemic spectrum consists of—in order of increasing wave
immunologic consequences, and some of these frequency and decreasing wavelength—radio,
immunologic sequelae may be important in the infrared, visible light, ultraviolet, x-ray, gamma ray,
pathogenesis of human skin cancers. and cosmic ray waves. The ultraviolet band com-
Toda and coworkers36 report decreased NK-cell prises the middle of the spectrum and is further
activity of nude mice receiving long-term ultravio- divided into UVA (400–315 nm), UVB (315–290
let radiation. This observation suggests impaired nm), and UVC (290–200 nm).47 The visible light
immunity and enhanced susceptibility to tumor waves have a frequency of 400–700 nm and the
induction by UV light in this athymic animal model. infrared band begins at 700 nm (Fig 1).
The main role of Langerhans cells and Leu-M5+
cells may be that of antigen presentation, while B
cells and NK cells probably play a minor role in the
local defense against BCC proliferation.
Immunosuppressive agents commonly used for
the treatment of many diseases and in transplanta-
tion medicine have been increasingly linked to the
development of spontaneous malignancies. 37
Immunosuppression depresses the immune sur-
veillance system that scavenges newly transformed
malignant cells. Approximately 30% of the skin
tumors arising in immunosuppressed patients are
highly aggressive.38
Immunosuppression also occurs with occult
malignancy and HIV infection. Senescence is a
form of immunosuppression. As mechanisms Fig 1. The electromagnetic spectrum.

4
 SRPS Volume 9, Number 5

In terms of skin cancer pathogenesis, the only • People engaged in outdoor activities are at
clinically significant wavelengths are in the ultravio- higher risk of skin cancer than those who spend
let spectrum. The ozone-rich stratosphere effec- most of their time indoors.
tively absorbs UV wavelengths below 290 nm, so • Individuals who have genetic disorders involv-
that only UVB and UVA reach the earth’s crust. ing decreased melanin production or impaired
Over 95% of solar UV radiation reaching the earth’s DNA repair are at higher risk of skin cancer.
surface is in the UVA waveband; the rest is UVB.
• Increasing rates of nonmelanoma skin cancer
The solar radiation that penetrates the atmosphere
occur with decreasing latitude and increasing
is almost devoid of UVC.
altitude.
UVB rays are the most carcinogenic and have
the most profound effect on skin cells. UVB induces
skin cancer through direct photochemical damage
Ionizing Radiation. The carcinogenic effect of
to cutaneous DNA, injury to DNA repair mecha-
excessive radiation exposure was recognized in
nism, and partial suppression of cellular mediated
1902, when skin cancer developed in a radiology
immunity.48,49
technician. Many studies demonstrate this rela-
UVA, which was initially thought to be harmless,
tionship.53-55 The most important factor appears to
is now known to potentiate the effects of UVB and
be the total accumulated dose. Reports abound in
to act as a potential co-carcinogen.50 Exposure to
the literature of skin carcinoma arising in uranium
high doses of UVA for a significant time can induce
miners, airline pilots, and patients treated with
cancer in laboratory mice.51 Infrared energy also
radiation therapy.3 One study showed a fourfold
seems to accelerate the carcinogenic process:
increase in the rate of basal cell carcinoma in white
Animals kept in heated environments develop
subjects exposed to therapeutic irradiation com-
tumors more rapidly than those in temperate cli-
pared with dark-skinned subjects receiving similar
mates.4 Wind and high humidity also increase the
dosages.55
amount of UV damage and rate of tumor forma-
Ionizing radiation acts as a co-carcinogen and
tion. Although the sun is the natural source of UV
increases the expression of skin cancer among UV-
radiation, the long-term effects of artificial UVA
sensitive subjects. In fact, ionizing radiation-induced
radiation from tanning lamps cannot be ignored.52
skin cancers occur more frequently in global regions
UVC is a potent carcinogen but is fortunately
with higher UV exposure.
filtered out by the ozone layer in our atmosphere.
As the ozone layer thins from the use of fluorocar-
bons, more UVC will penetrate the atmosphere
Chemicals. Certain chemicals increase the risk
and UVC will become a new factor in the develop-
of skin cancer either by acting as direct carcino-
ment of skin cancer. The depleted ozone layer will
gens or by enhancing the deleterious effects of
also allow more UVB to reach the earth, poten-
UV radiation. Polycyclic aromatic hydrocarbons
tially increasing skin cancer rates by 12% to 36%
and dimethyl benzanthracene, both atmospheric
after the year 2050.3
pollutants, have been shown to increase the rate
Strom and Yamamura3 provide an excellent
of skin cancer in exposed individuals.56 Nitrogen
review of the evidence for sun-induced skin car-
mustard and nitrosourea, both antineoplastic drugs,
cinogenesis, which proves beyond a doubt that
are carcinogenic and act synergistically with UV
UV radiation is the primary cause of nonmelanoma
radiation. Psoralens, used in the treatment of pso-
skin cancer. The evidence can be briefly summa-
riasis, in combination with UVA produce a dose-
rized as follows:
dependent increase in incidence of squamous cell
• Nonmelanoma skin cancer is mainly a disease carcinoma.57,58 Recently a case of squamous cell
of white people. It is rare in ethnic groups carcinoma arising from a hydrochloric acid burn
possessing melanin. scar was reported.59
• Fair-skinned populations that sunburn easily have Chronic arsenic exposure is associated with
high rates of nonmelanoma skin cancer. Most delayed occurrence of skin cancer.60,61 Arsenic
skin cancers appear on sun-exposed regions of had once been used in the treatment of asthma,
the body. syphilis, and psoriasis. These cancers appear 18 to

5
SRPS Volume 9, Number 5
45 years following exposure. The lesions are mul-
tiple, occur on unexposed regions of the body,
and are associated with hyperpigmentation and
keratoses.
PREVENTION OF NONMELANOMA
SKIN CANCER
Since exposure to solar radiation is a major cause
of nonmelanoma skin cancer, prevention is pos-
sible through avoidance. Preventive measures fall
into three general types: sunscreens, clothing, and
education. The efficacy of sun protection is mea-
sured by its sun protection factor (SPF). The SPF is
the ratio of the least amount of UVB radiation
required to produce erythema on protected skin
compared to the amount of UVB required to pro-
duce the same amount of redness on unprotected
skin.
Sunscreens
Because actinic damage is cumulative, protec-
tion from the sun is particularly important in the
young. Application of sunscreens in the pediatric
population is associated with an 80% reduction in
UV-induced skin damage and estimated similar
decreases in subsequent neoplastic changes.62 Even
in the elderly who already have considerable actinic
damage, studies show decreasing incidence of
actinic keratoses and most likely neoplasia with the
use of sunscreens.63,64
Sunscreens function either chemically or physi-
cally. Chemical sunscreens absorb UV radiation,
particularly UVB, thereby reducing skin penetrance
by UV radiation. The most common chemical sun-
screen ingredients are para-aminobenzoic acid
(PABA), benzophenones, and cinnamates. PABA
works by penetrating the stratum corneum, where
it remains attached through hydrogen bonding
while absorbing UV radiation. Older chemical sun-
screens absorbed only UVB, whereas today broad
spectrum (both UVA and UVB) coverage is avail-
able.65,66
Physical sunscreens reflect UV radiation by pro-
viding a physical barrier. Common physical sun-
screens are opaque agents such as titanium diox-
ide, zinc oxide, and kaolin. These products pro-
vide the best protection. Transparent zinc oxide is
6
now sold commercially, giving consumers an alter-
native to the telltale “lifeguard nose.”
Like all pharmacologic agents, sunscreens must
be applied properly. An adequate dose consists of
2 mg/cm2 of skin surface area. All sun-exposed
skin must be covered, including ears, lips, and
scalp.67 A major factor when selecting a sunscreen
is resistance to sweating and water immersion, a
property determined by carrier agents. Frequent
reapplication is necessary.
Useful sunscreens should have an SPF of at least
15. Products with SPF higher than 15 may offer no
clinical benefit.67,68 In addition, the public must be
reminded that the use of sunscreens is by no means
permission to go out under the sun for prolonged
periods of time: Sunscreens only provide a mecha-
nism to reduce actinic damage.
Clothing
Regular clothing provides scant protection
against UV radiation. A cotton T-shirt has an SPF of
less than 10 that decreases sharply when the cloth
is wet.69 High-SPF apparel is available, but tends to
be expensive, restrictive, and not commonly
worn.67,70 Closely-woven hats offer protection so
long as they have a wide brim or extra long bill
covering the face and neck.
Education
Physicians must instruct their patients about
photodamage, emphasizing the deleterious effects
of UV exposure and urging sensible ways to pro-
tect skin from the harmful effects of the sun. For
example, people should be warned that regular
window glass blocks all UVB rays but only 50% of
UVA radiation, and that a thin cloud cover only
reduces UV radiation by 20% to 40%, thus allow-
ing sun damage even during light rain. In addition,
education regarding tanning beds is imperative.
Although UVB radiation is filtered out, the UVA
radiation present in tanning beds is in fact higher
than that occurring in natural sunlight. Patients at
risk for nonmelanoma skin cancer must be particu-
larly alert for the appearance of suspicious lesions.
The following guidelines for photoprotection are
helpful:67
• Wear daily sunscreen with an SPF of at least 15.
All exposed skin must be covered, including the

lips, scalp, and ears. The sunscreen should be
applied 15-30 minutes before sun exposure and
reapplied every 2 hours.71,72
• Reapply sunscreen after swimming or heavy
sweating.
• Avoid outdoor activity during peak tanning/burn-
ing hours.
• Wear additional sun-protective apparel.
• Do not use tanning beds.
• Have regular dermatologic examinations.
• Teach sun protection to others.
Evidence shows that educational programs suc-
cessfully reduce UV radiation exposure.70,73
DIAGNOSIS
The procedure of choice for diagnosing
nonmelanoma skin cancer is shave excision or
incisional biopsy. This method is quick, produces
an adequate specimen for histologic study, and
gives an excellent cosmetic result should the lesion
turn out benign. Only rarely is an excisional biopsy
necessary when dealing with suspected BCC or
SCC, in contrast to melanoma which should gener-
ally be biopsied full thickness.
Torres74 notes that once a lesion has been
biopsied and appears to resolve clinically, a second
biopsy is unreliable in assessing the need for fur-
ther treatment. Mohs micrographic surgery found
residual tumor in 63% of cases deemed clear on
subsequent biopsy. It is therefore recommended
that curative surgery should proceed as originally
planned despite a clinically healed biopsy site and
no obvious tumor.
BASAL CELL CARCINOMA
The first description of a basal cell carcinoma
was by Jacob75 in 1827, who coined the term
“rodent ulcer”. In 1903 Krompecher76 listed the
histologic characteristics of what was initially
believed to be a true epithelial carcinoma.
Adamson77 is credited with suggesting, in 1914,
that BCC were nevoid tumors originating from latent
embryonic foci when aroused from their dormant
state. Lever78,79 concurred and classified the tumors
as hamartomas consisting of incompletely differen-
tiated immature basal cells. Pinkus80 postulated a
SRPS Volume 9, Number 5
different origin for basal cell carcinomas: The can-
cer arose from pluripotential cells in the epithelium
that were somehow provoked into malignant trans-
formation.
Further support of the hamartomatous charac-
ter of BCC came from two experimental studies.
Gerstein81 demonstrated that transplanted BCC to
the rabbit cornea do not grow, while squamous
cell carcinoma grafts do. Van Scott and Reinertson82
confirmed survival of BCC autotransplants only
when they included connective tissue stroma.
More recently, human basal cell carcinoma has
been transferred into athymic, asplenic mice, achiev-
ing approximately a 50% take.83-85 Attempts to
culture basal cell carcinoma tumors with explant
and suspension techniques have been largely suc-
cessful. The cultured cells tend to develop charac-
teristics of differentiation that are unlike those of
the host’s own tumors.86 At this time the signifi-
cance of BCC cell culture is still unclear.
Tumor Biology
Basal cell tumors originate in the pluripotential
epithelial cells of the epidermis and hair follicles.
The cell cycle of a BCC is about 217 hours (9
days),87,88 which means that a tumor would be
expected to double in volume every few weeks.
That is not the case, however. Basal cell carcino-
mas, in fact, tend to grow slowly and take months
or years to reach a large size.
Grimwood and coworkers89 used radioactive
thymidine to study this apparent discrepancy and
showed that only the outer cells of a tumor nodule
(including the palisade layer) were actively divid-
ing. Their observation underscores the importance
of adequate extirpation of the peripheral exten-
sions of a nodular BCC, since transection leaves
behind precisely the most actively dividing portion
of the tumor and could be the reason why recur-
rent tumors are more aggressive.
Morpheaform basal cell carcinomas have the abil-
ity to synthesize type 4 collagenase, which may
enhance their aggressive behavior. Other features
of a tumor that may contribute to invasiveness82,90-94
include
• decreased membrane continuity
• decreased amyloid production
• increased numbers of actin microfilaments
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SRPS Volume 9, Number 5

• increased tetraploid DNA configuration years, and more than 50% occur in men. Shanoff,
• increased collagen synthesis Spira, and Hardy99 reported a tumor distribution by
anatomic site that is representative of all BCC (Fig 2).
• increased tumor fibroblasts The head and neck areas account for 93% of all
Basal cell tumors are stroma-dependent. Experi- BCC (Fig 3), with the highest incidence of BCC on
mentally transplanted BCC, free of dermal tissue, the nose (26%). Other authors confirm this pattern
do not survive.95 Perhaps the altered stroma of of tumor distribution.100-103
scarred tissue incites the pluripotential cells to A subsequent report from Australia,104 which
become malignant, explaining the occurrence of ranks first in the world for prevalence of BCC, shows
tumor in areas of trauma, ulcers, and burns.96,97 a trend toward a greater proportion of lesions
Basal cell carcinomas have been experimentally occurring in the trunk and extremities.
produced in rats by means of chemical carcino-
gens, but it has never been possible to reproduce Histologic Types
the tumors with UV light energy alone.
Wade and Ackerman105 identify 26 different variet-
ies of basal cell carcinoma. Most histologic subtypes
Epidemiology generally conform to the clinical picture (Fig 4).
In North America the various histologic types
Basal cell carcinomas occur almost exclusively in occur with the following frequency:106
light-skinned people. The typical patient has fair hair, nodular 50%–54%
fair skin, blue eyes, spends a great deal of time out- superficial 9%–11%
doors, and sunburns easily. Abreo98 reported basal cystic 4%–8%
cell carcinomas in 26 African American patients, but adenoid 1%–7%
one was an albino, another had a history of burn, pigmented 6%
and a third had a long-standing stasis ulcer. About morpheaform 2%
95% of cases occur between the ages of 40 and 79 atypical 1%

Fig 3. Locations of new and recurrent lesions on the head by

Fig 2. Location of lesions studied. (Reprinted with permission anatomical units. (Reprinted with permission from Shanoff LB et
from Shanoff LB et al: Basal cell carcinoma: a statistical approach al: Basal cell carcinoma: a statistical approach to rational
to rational management. Plast Reconstr Surg 39:619, 1967.) management. Plast Reconstr Surg 39:619, 1967.)

8

Fig 4. Histologic types of basal cell carcinoma. (After Jacobs GH, Rippey JJ, and Altini M: Prediction of aggressive behavior in basal
cell carcinoma. Cancer 49:533, 1982.)
The aggressive nature of some histologic vari-
ants, particularly the ulcerative and infiltrative
tumors, has been widely reported. Jacobs, Rippey,
and Altini107 investigated this phenomenon and
concluded that aggressive tumors are characteris-
tically more ulcerative than infiltrative. Sclerosing
lesions represent a distinct, more aggressive vari-
ant of BCC.
Sexton, Jones, and Maloney108 analyzed 1039
basal cell carcinomas and found that the micro-
nodular, infiltrative, and morpheic lesions had the
highest incidence of tumor remaining at the mar-
gins after simple surgical excision.
Clinical Types
Superficial BCC lies within the epidermis with-
out dermal invasion. The lesion is erythematous
and scaly. On careful examination the tumors may
be seen to have a thread-like border, some may
exhibit a shallow ulcer or crusting, and others yet
may show atrophic scarring. In their early stages
these tumors are frequently confused with eczema
or a fungal infection.
Nodular BCC, the most common subtype, begins
as a flesh-colored nodule on the surface of the skin
with small telangiectatic vessels coursing through-
out. Initially it seems so innocuous that it may be
easily mistaken for a dermal nevus or other benign
skin tumor. The so-called rodent ulcer resembles
nodular BCC except that it tends to be more deeply
seated, and characteristically it presents as a slowly
SRPS Volume 9, Number 5
enlarging central ulcer surrounded by a rolled,
pearly border.
Pigmented BCC is told apart from the nodular
variety by its brown pigmentation, for which mela-
nin is primariy responsible. The color is sometimes
intense, appearing on the surface as almost blue-
black, and for this reason pigmented BCC are often
confused with melanomas.
Morpheaform or sclerosing BCC presents as a
firm, white or yellowish plaque with an ill-defined
border. Patients tend to describe it as an “enlarg-
ing scar” that cannot be accounted for by any ante-
cedent trauma. Induration is always present and
ulceration is extremely rare. Morpheaform BCC is
frequently misdiagnosed and can grow to be quite
large without showing more than 1–2 mm eleva-
tion above the skin surface. This tumor most fre-
quently has positive margins following simple sur-
gical excision.
There is no such thing as a multicentric basal cell
carcinoma: By definition this means the tumor
must be arising from many different foci, and that is
not case. Kimura109 and Zackheim110 showed that
the nests of tumor cells in “multifocal” BCC, though
seemingly disconnected on superficial examination
and on routine histologic sections, in fact are con-
nected along the rete ridges.
Similarly, the entity called “basosquamous carci-
noma” remains controversial. Pathologists have
traditionally used this term when at a loss to distin-
guish between a basal cell and a squamous cell
9
SRPS Volume 9, Number 5

carcinoma, in which case the most likely diagnosis recommend lateral margins of 5 mm when excis-
is usually a keratotic BCC or small-cell SCC. ing a basal cell carcinoma. This rule of thumb works
for small nodular lesions, but cure rates sharply
decline when dealing with larger tumors or with
Treatment
fibrosing, morpheaform, and infiltrative tumors.
The treatment of BCC falls within three broad
categories: surgical, destructive, and medical (in- TABLE 3
cluding irradiation). Recurrence of BCC Treated with Surgical Excision
Surgical treatment involves either primary surgi-
cal excision or Mohs micrographic surgery and is
appropriate for nearly all cases.
Destructive treatment literally destroys tissue and
therefore does not permit pathologic review. This
technique is indicated for superficial lesions only
and for patients who are poor candidates for sur-
gery. Destructive techniques include electrodesic-
cation and curettage, cryosurgery, and laser photo-
therapy.
Medical treatment is administered with the hope
of altering the course of the BCC. These tech-
niques include experimental methods of intra-
lesional interferon injection and topical chemo-
therapy, neither of which is very efficacious in achiev-
ing a cure. Radiotherapy, although an effective
medical intervention, unfortunately has many
undesirable side effects.

Surgical Treatment

Primary Surgical Excision

Surgical excision is the time-honored treatment
method in skin cancer, with cure rates averaging
90%111 (Table 3). Dubin and Kopf112 obtained an
overall cure rate of 91% in BCC treated by surgical
excision. The likelihood of a cure decreased as the
size of the lesion increased.
Epstein113 found that visual assessment of the
margins of a BCC was within 1 mm of the actual
border in 94% of cases. This observation led him
to conclude that a 2-mm margin gave a 94% cure
rate. In contrast, Burg and coworkers114 compared (Reprinted with permission from Dubin N, Kopf AW: Multivariate
the clinical size of a tumor as estimated by the risk score for recurrence of cutaneous basal cell carcinomas. Arch
Dermatol 119:373, 1983.)
naked eye with its true size as determined by Mohs
micrographic examination, and found the difference
to be 5.5 ± 3 mm for primary BCC and 8.9 ± 4.8 Sexton, Jones, and Maloney108 analyzed 1039
mm for recurrent BCC. Wolf and Zitelli115 found basal cell carcinomas and correlated the histologic
that for tumors with a diameter of <2 cm, a mini- type of tumor with adequacy of surgical excision.
mum margin of 4 mm was needed to totally eradi- They found that nodular and superficial BCC can
cate the tumor in 95% of cases. Most authors be completely removed by simple surgical exci-

10

sion in a high percentage of cases—93.6% and
96.4%, respectively. In contrast, micronodular,
infiltrative, and morpheaform lesions are associated
with positive tumor margins in 18.6%, 26.5%, and
33.3% of cases. Mixed tumor patterns consisting
of combinations of nodular, micronodular, and
infiltrative types were also at high risk of recur-
rence from incomplete surgical removal.
Mohs Micrographic Surgery
The Mohs micrographic surgery technique was
developed by Frederick Mohs116 in 1932. Mohs
originally called the technique “chemosurgery”
because it combined zinc chloride as a fixative
(chemo-) and microscopic control of the excisional
margins created with a knife (-surgery). The tech-
nique was not widely accepted until 1970, when
Tromovitch117 presented his results with the fresh-
tissue modification, which does not involve a chemi-
cal fixative.
As performed today, Mohs micrographic sur-
gery involves excision of all visible tumor in saucer-
like layers while mapping the exact size and shape
of the lesion. Horizontal frozen sections taken
from the undersurface of the excised tissue are
examined microscopically: Wherever tumor is
found, it is localized on the “map” and the area
marked for further resection. This process is
repeated until all tumor is removed118 (Fig 5).
The advantages of Mohs micrographic surgery
for excision of skin tumors are high cure rates,
decreased morbidity, and significant tissue conser-
vation. The only disadvantage is the need for two
separate surgeries when reconstruction is required,
which adds cost and inconvenience to the patient.
In many cases conventional frozen section can be
just as effective in detecting residual tumor foci.
The indications for Mohs micrographic surgery
in the treatment of malignant skin tumors118 are as
follows:
• primary lesions meeting one or more of the
following criteria:
a) tumors in sites reported to have a relatively
high rate of treatment failure—eg, periorbital
and periauricular areas, nose and paranasal
area
b) tumors with poorly delineated clinical bor-
ders or arising from scar tissue
SRPS Volume 9, Number 5
c) tumors with aggressive malignant features
d) morpheaform or sclerosing basal cell carcino-
mas
e) tumors in critical locations such as the eyelid,
where it is desirable to preserve as much
uninvolved tissue as possible
f) squamous cell carcinomas with perineural
invasion
• recurrent basal cell and squamous cell carcino-
mas
• microcystic adnexal carcinoma
• dermatofibrosarcoma protuberans
Cure rates for primary BCC treated by Mohs
micrographic surgery are 99%.118 Figure 6 shows
the lateral surgical margins that are needed to obtain
cure rates of 75%, 85%, and 95% as tumor size
increases. These figures are based on horizontal
frozen sections obtained from nearly 8000 cases
of primary basal cell carcinoma treated by Mohs
micrographic surgery.119
The cosmetic results of delayed primary recon-
struction after resection of basal and squamous
cell carcinomas by Mohs micrographic surgery are
excellent.120
Destructive Treatment
Electrodesiccation and Curettage (EDC)
EDC is the most common method for treatment
of basal cell carcinoma, with reported cure rates as
high as 96% to 100%.121 When the effectiveness
of EDC treatment is analyzed by tumor size, how-
ever, it is evident that lesions <2 mm in diameter
are completely removed 100% of the time, lesions
2–5 mm in diameter are eradicated 85% of the
time, and tumors >3 cm recur in 50% of patients,
for an overall cure rate of 74%.112 Dubin and
Kopf112 recommend EDC only for very small and
superficial tumors.
Cryosurgery
Cryosurgery was first used for the treatment of
skin tumors around the turn of the century122 but
was soon abandoned because an adequate closed
system for delivery of the coolant was lacking.
Some 60 years later, cryosurgery was reintroduced
into this country, and since then it has been used
11
SRPS Volume 9, Number 5
Fig. 5. Mohs micrographic surgery, fresh-tissue technique.
(After Cottel WI, Proper S: Mohs’ surgery, fresh-tissue technique.
Our technique with a review. J Dermatol Surg Oncol 8:576, 1982.)
extensively by practitioners such as Zacarian,123 who
formulated guidelines based on his experience with
4228 tumors. Zacarian lists the following indications
for cryosurgery in the treatment of skin cancer:
12
Fig 6. Margins and cure rates obtained with Mohs micrographic
surgery in primary BCC by size. (Data from Cottel WI, unpub-
lished, 1992.)
• nodular or ulcerated carcinomas
• tumors with well-defined borders by palpation
or instrumentation
• most tumors overlying bone or cartilage
• selected lesions of the eyelid
• tumors on the tip of the nose
• recurrent tumors after radiotherapy
• lentigo maligna
• elderly patients who are poor surgical risks
• patients who have idiosyncrasies to anesthesia
• palliation in advanced tumors
Cryosurgery is acceptable for the treatment of
skin tumors when these indications are closely
adhered to and the operator is adequately trained
in cryosurgery. In Zacarian’s hands the overall
cure rate was 97.4%, but only 10% of the lesions
he treated were >2 cm.123 Of the 110 tumors that
recurred, 33% had been previously treated by other
means.
Absolute contraindications to cryosurgery are
• patients with abnormal cold intolerance such as
cryoglobulinemia or cryofibrinogenemia
• morpheaform or sclerosing basal cell carcinoma
Relative contraindications include
• neoplasia of the scalp
• lesions of the ala nasi and nasolabial fold

• tumors anterior to the tragus and postauricular
sulcus
• tumors on the free margin of the eyelids
• neoplasia near the vermilion border of the lip
• tumors of the lower leg
• nodular or ulcerative lesions >2 cm in diameter
• carcinomas fixed to bone or underlying carti-
lage
• tumors on the lateral margins of the fingers and
at the ulnar groove of the elbow
• recurrent carcinomas after surgical excision
Complications of treatment with cryosurgery
include marked edema, a long period (4–6 weeks)
of morbidity, and permanent pigment loss at the
site of treatment. Hypopigmentation and atrophic
and hypertrophic scars are seen. At times there
may be neuropathic changes in certain areas, par-
ticularly the fingers and elbow. Cryosurgery is best
reserved for small lesions.
Pulsed CO2 Laser
High-energy short-pulsed CO2 laser permits
superficial vaporization of tissue in a controlled fash-
ion. For superficial BCC that is confined to the
epidermis and papillary dermis only, treatment with
the pulsed CO2 laser can ablate the lesion and limit
neighboring thermal damage. At settings of 500
mJ and 2–4 W, the pulsed CO2 laser typically
vaporizes the epidermis to within 20–30 mcm; the
second pass destroys most of the papillary dermis;
and the third pass (reduced to a setting of 450 mJ)
enters the deeper papillary dermis and can expose
reticular dermis. Because damage to the surround-
ing tissue is kept to a minimum, the potential for
scarring is theoretically reduced.
Pulsed CO2 laser ablation is a potentially favor-
able technique in superficial BCC.124 Appropriate
treatment requires three passes on clinically visible
tumor with treatment of at least 4 mm of surround-
ing healthy skin.125
It is debatable whether the cosmetic results of
laser phototherapy are better than those obtained
with surgical methods. Adverse effects of the laser—
including hypopigmentation and scarring—are more
common when treating nonfacial sites. An obvi-
ous disadvantage of laser treatment, as of all
destructive techniques used to treat superficial BCC,
SRPS Volume 9, Number 5
is the inability to examine pathologic margins. Laser
treatment of tumors extending deeper than the
epidermis or superficial papillary dermis is inappro-
priate because of scarring and inability to assess
the margins for residual tumor.
Medical Treatment
Intralesional Interferon Injection
Interferons are a family of proteins with antiviral
activity that are currently being studied for their
possible application in cancer prevention and treat-
ment. They are known to interfere with viral repli-
cation, inhibit cell growth, effect cell differentiation,
and modulate a variety of other immunologic and
cellular functions. Alfa-2 interferon has been used
in the treatment of BCC, melanoma, cutaneous
lymphoma, condyloma, and Kaposi’s sarcoma.
In 1986 Greenway and associates126 injected
recombinant alfa-2 interferon intralesionally in eight
patients with biopsy-proven superficial or nodular
BCC. The tumors varied in size from 7 x 6 mm to
14 x 12 mm; each lesion was injected three times a
week for 3 weeks. Tumor regression of 52% to
100% (avg 77%) was noted in all cases. Systemic
side-effects of treatment consisted of mild to mod-
erate flu-like symptoms, which were controlled with
acetaminophen. Local reaction, which was limited
to erythema and itching at the site of injection, was
treated with cold compresses.
Cornell and associates127 reported the results of
a multicenter trial in which 172 patients had their
BCC injected with intralesional interferon. The larg-
est test lesions was 0.5–1.5 cm (if noduloulcerative)
and 0.5–2 cm (if superficial). After one year, 81%
of the patients remained tumor-free. Other investi-
gators128–133 cite cure rates in the 75% to 80%
range with alfa-2 interferon.
Stenquist and others134 treated 15 aggressive,
large basal cell carcinomas with intralesional inter-
feron alfa-2b. The authors concluded that at the
dosage given, interferon was able to cure only a
very small percentage of aggressive basal cell car-
cinomas.
In another study, Edwards and colleagues135 tried
interferon gamma on basal cell carcinomas and
obtained only a 50% cure rate. At this time,
intralesional interferon remains an experimental
method of treatment producing much lower cure
rates than can be achieved by other means.
13
SRPS Volume 9, Number 5

Chemotherapy TABLE 4
Recurrence of BCC Treated with X-ray Therapy
Topical chemotherapy with 5-fluorouracil for the
treatment of any potentially invasive skin cancer
should be mentioned only to be condemned.136
The time required for adequate treatment is inordi-
nately long and carries a high morbidity, and cure
rates are inadequate despite the most careful tech-
nique. Topical chemotherapy is established, how-
ever, in the treatment of premalignant lesions such
as AK.

Radiotherapy
Therapeutic irradiation claims an overall cure rate
of 92% in the treatment of skin malignancies112
(Table 4). The technique requires specialized per-
sonnel and equipment as well as prolonged dura-
tion of treatment.
Although radiation produces few cosmetic
defects initially, the results deteriorate over time,
and fibrosis, ectropion, and ulceration are not
uncommon sequelae.137 There is even a small
risk of radiation osteitis and chondritis on treat-
ment of certain areas. In short, radiation should
be reserved for elderly patients who are not sur-
gical candidates, as it is a relatively safe and
nonvasive modality but one that has potential long-
term consequences.

Large Tumors
Large skin tumors are a challenge to resect and
reconstruct. Excision under local anesthesia in an
outpatient setting may be inappropriate for some
of these large lesions. Additionally, when the tu-
mor abuts bone or vital structures such as the eye,
the surgeon may be forced to terminate the proce-
dure prematurely. Large tumors, therefore, are
best treated in the operating room by a team of
skilled specialists, as follows:
• the Mohs surgeon resects peripheral margins
• deeper regions are resected by a surgeon fa-
miliar with the anatomy
• the Mohs surgeon inspects the dermopathologic
sections
• the plastic surgeon reconstructs the normal
anatomy of the area
(Reprinted with permission from Dubin N, Kopf AW: Multibariate
risk analysis score for recurrence of cutaneous basal cell carcino-
mas. Arch Dermatol 119:373, 1983.)
This team approach maximizes patient comfort,
decreases cost, and improves efficiency.138
Single-stage surgical excision using a modified
frozen-section technique similar to Mohs section-
ing has also been described.139
Incompletely Excised BCC
Occasionally a tumor has been resected, the
frozen section is read as negative, and the defect is
closed. The final pathology report subsequently

14

returns with a positive margin, leaving the treating
physician in a quandary. In the absence of gross
disease, when permanent histologic examination
finds residual tumor, the treating physician faces
several options: re-excision, observation, or radia-
tion therapy.
A number of authors140-146 estimate that approxi-
mately one-third of all incompletely excised BCC
will recur. Some investigators have found a con-
siderably higher recurrence rate for incompletely
excised BCC;99,143,144 indeed, one such study99
found a recurrence rate as high as 67%. Pascal
and colleagues142 state that when tumor is within
one high-power field (400X) of the surgical margin,
12% of lesions recurred, whereas a 33% recur-
rence rate exists when tumor actually involves the
surgical margin.
Liu and associates147 examined 187 incompletely
resected basal cell carcinomas. The 5-year prob-
ability of tumor recurrence was 17% when the
lateral margin was positive and 33% when the deep
margin was positive. Their study excluded cases
with clinical evidence of remaining gross disease.
Dellon and associates148,149 correlate histologi-
cal appearance of tumor with likelihood of recur-
rence in incompletely excised BCC. The authors
found that irregularities in the peripheral palisades
were indicative of tumor aggressiveness. When
more than 75% of the tumor cords in the positive
margin specimen contained irregularities in the
peripheral palisade, the tumor had a greater than
95% probability of recurrence, and re-excision was
recommended. On the other hand, if fewer than
25% of the tumor cords in the positive-margin speci-
men contained irregularities in the peripheral pali-
sade, the tumor had a 95% chance of not recur-
ring, and close follow-up was suggested. The
chance of recurrence in the intermediate group—
those having between 25% and 75% of tumor
cords with irregularities in the peripheral palisades—
depended on the degree of lymphocytic infiltra-
tion.
Robins and Albom150 note that BCC is much
more likely to recur in young women, a fact they
attribute to the conservative margin taken during
the resection in an attempt to give these patients a
better cosmetic result.
Griffiths151 examined all re-excised BCC speci-
mens from lesions with incompletely excised mar-
gins at the first surgery. He found 54% of the scar
SRPS Volume 9, Number 5
specimens showed residual tumor on histologic
examination.
Koplin and Zarem101 state that the key consider-
ations in treating skin cancer are complete excision
of the lesion and preservation of as much normal
tissue as possible. The authors convincingly argue
that when dealing with incompletely excised BCC,
large amounts of normal tissue will be replaced by
recurrent tumor by the time the lesion is brought
to the attention of the treating physician. Addition-
ally, since an early recurrent tumor and a normally
healing wound are similar in appearance, the physi-
cian is left in an awkward position. Koplin and
Zarem recommend immediate re-excision of all
lesions with positive margins as soon as the wounds
are adequately healed.
Close observation of incompletely excised BCC
is a management option far from ideal. Of the
30% of patients with incompletely excised BCC
whose lesions will recur, 85% will have recur-
rence within 3 years of the primary surgery.152
Others report recurrences later than expected,
with only 66% of lesions returning in the first 3
years.153 These statistics have led some authors
to suggest that close initial follow-up is adequate
surveillance. However, issues such as frequency
of required follow-up visits, duration of follow-up,
increased financial cost of protracted care, psy-
chological cost to the patient from the risk of
possible recurrence, and the need for multiple
biopsies have not been thoroughly investigated.
Patients with incompletely excised margins who
are lost to follow-up represent a high-risk group,
and certainly the current medicolegal atmosphere
must be considered too. Griffiths151 argues that
since the overall incidence of incompletely excised
BCC is often low and the risk of recurrent BCC
real, the most efficient course of action is to re-
excise the incompletely resected lesions and dis-
charge the patient.
In the event the patient or surgeon is reluctant
to proceed with re-excision but still desires thera-
peutic intervention beyond simple observation,
radiotherapy may have a role in preventing recur-
rence.154 This is unequivocally a poor line of treat-
ment for incompletely excised BCC, yet one that
some patients may deem acceptable regardless of
the expense, prolonged treatment time with mul-
tiple visits, absence of firm pathologic diagnosis,
and posttreatment fibrosis.
15
SRPS Volume 9, Number 5
Recurrent Tumors
Basal cell tumors in certain anatomic locations
like the periorbital, perinasal and periauricular
regions often recur despite adequate treatment
(Figs 7 and 8).99 In these sites only 75% to 80% of
lesions are cured on first treatment.
The reasons for these high rates of tumor recur-
rence by anatomic site are multiple and specula-
tive. For instance, various hypotheses implicate
the relationship of BCC to embryologic fusion
planes; a tendency to spread subcutaneously but
rarely to invade the periosteum or perichondrium;
difficulty in accurately assessing the extent of the
tumor during surgical excision; and lack of adequate
margins during the resection for fear of needlessly
destroying a vital anatomic structure or facial land-
mark. Other reasons are more obscure and have
to do with some inherent property or growth habit
of the lesions: Tumors occurring in some places
(eg, the forehead) as well as certain histologic types
of tumor (eg, morpheaform and sclerosing) show
a proclivity for large subclinical extension. Robinson
and colleagues 97 dispute the persistence of
Fig 7. Location of lesions studied. (Reprinted with permission
from Shanoff LB et al: Basal cell carcinoma: a statistical approach
to rational management. Plast Reconstr Surg 39:619, 1967.)
16
embryologic fusion planes and their relation to
recurrences of skin cancer.
Dixon and coworkers155 examined 631 cases of
recurrent BCC and found the most frequent sites
of occurrence were the nose, forehead, and temple.
Histologically the lesions were characterized by
absent to poorly formed peripheral palisading and
a marked degree of nuclear polymorphism. Of
recurring lesions, 27% presented a “spiky shaped”
pattern, compared with only 4% spikes in the non-
recurrent group. Tumors having infiltrative,
morpheaform, and superficial growth habits were
associated with the highest rate of recurrence.
Interestingly, there was no apparent difference in
degree of squamous cell change or metaplasia
between any of these groups.
Silverman and colleagues156–159 analyzed a 27-
year experience with basal cell carcinomas from
the standpoint of primary treatment as a factor in
recurrence. When lesions <9 mm in diameter were
removed by X-ray therapy,159 the 5-year recurrence
rate was 4.3%. When the tumors were >10 mm,
the recurrence rate was 13.7% (Fig 9).
Fig 8. Locations of new and recurrent lesions on the head by
anatomical units. (Reprinted with permission from Shanoff LB et
al: Basal cell carcinoma: a statistical approach to rational
management. Plast Reconstr Surg 39:619, 1967.)

Fig 9. Five-year recurrence rate of basal cell carcinoma of the
nose treated by X-ray therapy, plotted by size of the lesions.
(Data from Silverman MK et al: Recurrence rates of treated basal
cell carcinomas. Part 4: X-ray therapy. J Dermatol Surg Oncol
18:549, 1992.)
Recurrence after treatment with EDC ranged
from 8.5% to 26.1% depending on size of the
lesion157 (Fig 10).
Fig 10. Five-year recurrence rate of basal cell carcinomas
treated by electrodesiccation and curettage, plotted by size of
the lesions. (Data from Silverman MK et al: Recurrence rates of
treated basal cell carcinomas. Part 2: Curattage-electrodesic-
cation. J Dermatol Surg Oncol 17:720, 1991.)
For surgically excised BCC, recurrences on low-
risk sites became increasingly more frequent as the
original tumors became larger.158 When the data
were adjusted for tumor location, they found the
expected rise in recurrence rates with increasing
size of the primary lesion (Fig 11).
This study supports Dubin and Kopf’s112 recom-
mendation that basal cell carcinomas be treated
differently according to size, anatomic location, his-
tologic characteristics, and whether primary or
recurrent.
An excellent study by Rowe and associates160
demonstrates that contrary to popular belief, less
than one-third of recurrences appear within the
first year following treatment; 50% appear within
the first 2 years; and only 66% appear within the
first 3 years. In fact, 18% of recurrences appear
between the fifth and tenth year following treat-
SRPS Volume 9, Number 5
ment. These results were true for all modalities of
treatment. Thus lifetime follow-up is necessary after
removal of BCC.
Fig 11. Five-year recurrence rate of basal cell carcinoma of the
head treated by surgical excision, plotted by size of the lesions.
(Data from Silverman MK et al: Recurrence rates of treated basal
cell carcinomas. Part 3: Surgical excision. J Dermatol Surg Oncol
18:471, 1992.)
In the same publication the authors examined
the 5-year recurrence rate according to treatment
modality, and report their results as follows: Mohs’
micrographic surgery, 1.0%; surgical excision,
10.1%; electrodesiccation and curettage, 7.7%;
radiation therapy, 8.7%; and cryosurgery, 7.5%.
In another comprehensive study, Rowe and
associates161 conclude that Mohs micrographic sur-
gery is the treatment of choice for recurrent BCC.
The 5-year recurrence rate of recurrent (previously
treated) BCC following treatment with Mohs
micrographic surgery was 5.6% compared with
19.9% for those treated by other methods.
Scattered throughout the literature are reports
alluding to a unique subclass of basal cell carci-
noma recurring after radiotherapy. These recur-
rent tumors are said to be far more aggressive and
much more difficult to eradicate than recurrent BCC
previously treated by non-X-ray modalities. 162
Although the vast majority of these reports are
anecdotal, the perception continues and perhaps
has some validity.
Most surgeons who deal with recurrent BCC
also feel that tumors become more aggressive as
treatments multiply, evidenced by the change in
tumor histology from nodular to infiltrative as one
attempt at cure follows another. Two studies163,164
refute these beliefs, however, and show clearly
that the majority of recurrent BCC are aggressive
from the outset and do not become more aggres-
sive with each recurrence.
17
SRPS Volume 9, Number 5
Second Tumors
The estimated risk of developing one or more
new primary BCC or SCC of the skin is 35% at 3
years and 50% at 5 years.165,166 The new skin can-
cers tend to be of the same histologic type as the
previous ones. The risk increases with number of
previous skin cancers, solar damage, and skin sen-
sitivity. Patients who smoke have increased inci-
dence of squamous cell carcinoma.165 Moreover,
some note an increased risk of melanoma in
patients with a history of basal cell or squamous
cell carcinoma.167
Metastatic Tumors
Since the initial report by Beadles168 in 1894,
approximately 175 cases of metastatic BCC have
been documented in the literature, for an estimated
incidence of <0.1%.169 When a basal cell carci-
noma does metastasize, it is usually to the lymph
nodes, lungs, and bones. Lymphatic and hemato-
genous spread are equally frequent.170,171
BCC MIMICS
Trichoepithelioma
Trichoepithelioma should be considered in the
differential diagnosis of basal cell carcinoma. The
lesions are characteristically flesh-colored, papular,
solitary or multiple, small, and nonulcerative. Histo-
logically, trichoepithelioma is characterized by horn
cysts and basaloid proliferation of cells in the sur-
rounding stroma; it may be extremely difficult to
differentiate from a keratotic BCC. Immunologic
staining for CD34 may help in the diagnosis.172 A
classic trichoepithelioma has the following distin-
guishing features:173
• symmetrical tumor mass
• rare ulceration
• well-circumscribed lesion with smooth margins
• primitive hair structures
• no retraction spaces
• cornified cysts
• prominent fibrosis between and around aggre-
gates of basaloid cells
• rare inflammatory-cell infiltrates
18
Desmoplastic Trichoepithelioma
In 1977 Brownstein and Shapiro174 described 50
cases of a distinctive entity they named desmoplas-
tic trichoepithelioma. The lesions occurred mainly
in women and consisted of small, 0.3–1.0 cm lesions
that were typically hard and annular, with a raised
border and a central depression but without a cen-
tral ulcer. Histologically desmoplastic trichoepithe-
lioma shows cystic structures and basaloid cells
similar to a true trichoepithelioma; the stroma is
fibrotic. The basaloid cells tend to be in narrow
strands such as seen in morpheaform basal cell
carcinoma, with which it is frequently confused;
morpheaform BCC, however, rarely has the large
horn cysts characteristic of trichoepitheliomas.
Desmoplastic trichoepithelioma is completely
benign. The lesions are usually removed only for
diagnosis and to rule out malignant processes.
Eccrine Epithelioma
(BCC with Eccrine Differentiation)
Freeman and Winkelmann175 first described this
lesion in 1969. It typically occurs on the scalp but
may also be found in other sites within the head
and neck.
The clinical behavior of eccrine epithelioma is
very much like that of a basal cell carcinoma,
although histologically it resembles a syringoma.
The lesions are aggressive and tend to invade
underlying structures; recurrences are common.
Treatment of choice appears to be wide local exci-
sion with precise margin control or Mohs micro-
graphic surgery.176
Microcystic Adnexal Carcinoma
Microcystic adnexal carcinoma (MAC) was first
described by Goldstein and associates177 in 1982.
The tumors are characteristically found on the upper
lip, nose, and periorbital area of middle-aged men
and women. Histologically there are small cystic
structures with strands of basaloid cells similar to a
basal cell carcinoma; on close inspection these
basaloid cells tend to resemble the duct-like struc-
tures of eccrine glands.155 The lesions are locally
aggressive, and perineural invasion is the rule.
Recurrences after standard surgical excision are
common, and therefore wide local excision with
 SRPS Volume 9, Number 5

precise margin control or Mohs micrographic sur- much higher risk from SCC of the skin than other
gery is most suitable for treatment.178 physical types. The disease shows a predilection
for the sun-exposed extremities, head, and neck,
and may also arise in areas of scar from old burns,
SQUAMOUS CELL CARCINOMA
sinus tracts, and vaccinations. Freeman and Knox185
Squamous cell tumors rarely arise from unal- illustrate the anatomic distribution of SCC in their
tered, completely normal skin. On careful exami- series (Fig 12).
nation some premalignant change is usually seen,
such as sun damage, actinic keratoses, leukoplakia,
radiation keratoses or dermatitis, scars, chronic
ulcers, or sinuses.179 The tumors usually begin as
nodules that proceed to develop areas of necrosis
and oozing. Squamous cell cancers tend to be
more inflammatory, feel more indurated, grow more
rapidly, and ulcerate much sooner than basal cell
tumors.

Biology
Squamous cell cancers of the skin arise from the
malpighian or basal layer of the epidermis. The
growth rate of squamous cell tumors is much faster
than that of BCC, with SCC having a cell cycle of
only 50.2 hours.180 The mitotic index or cellular
turnover time of undifferentiated, anaplastic SCC,
however, is no higher than for well-differentiated
tumors.180 This lack of correlation between cell
cycle times and clinical growth of the lesions has
been linked to the observation that at any given
time some of the cells of a tumor are dividing while
others are dying;181 in other words, the entire tumor
Fig 12. Distribution of Squamous Cell Carcinoma by Anatomic
mass does not proliferate.
Site. (Reprinted from Freeman RG, Knox JM: Treatment of Skin
Cancer. Recent Results Cancer Res 2, 1967.)
Epidemiology
In the United States SCC of the skin is only one- Histologic Types
fourth as prevalent as BCC.182 Cutaneous SCC All squamous cell carcinomas of the skin are
show an even stronger correlation with damage to histologically similar, consisting of irregular masses
the skin by actinic radiation than BCC. The risk of of squamous epithelium that proliferate downward
developing SCC of the skin climbs proportionately to the dermis. The degree of cellular differentia-
with length of exposure to sunlight and is cumula- tion determines the grade of a tumor and is a mea-
tive with age.183,184 Because of the differences in sure of the ratio of atypical pleomorphic and ana-
incident sunlight and individual sun exposure plastic cells to normal epithelium. Changes in size
between the two countries, cutaneous SCC occurs and shape of the cells, hyperchromasia, keratiniza-
in 41 of 100,000 in the U.S., while in Australia the tion, and the proportion of mitotic figures influ-
annual incidence is 201 cases in 100,000. ence the determination of tumor grade: In the
Squamous cell carcinomas of the skin can be higher grades of tumor, cellular differentiation and
experimentally produced by UV light almost to the hence keratinization are greatly diminished, while
exclusion of other types of cancer. White-skinned mitoses are conspicuous and most cells are atypi-
persons of fair complexion and light hair are at cal, often spindle-shaped.

19
SRPS Volume 9, Number 5
Some highly anaplastic malignant skin tumors
are impossible to categorize by light microscopy
alone and must be further studied with the aid of
immunohistochemical assays,186 because the diag-
nosis dictates the course of therapy and prognosis.
Immunoperoxidase stains can distinguish between
desmoplastic melanoma and poorly differentiated
squamous cell carcinoma and other spindle cell
tumors. Further differentiation is possible with epi-
dermal cytokeratin antibody, which is specific for
tumors of squamous epithelium, and the antibody
to S-100 protein, which selectively stains melano-
cytes and Langerhans cells.
Clinical Types
Although initially the lesions may appear smooth,
verrucous, papillomatous, or ulcerative, given
enough time all SCC will exhibit induration, inflam-
mation, and ulceration.
Treatment
In general, treatment of a cutaneous squamous
cell carcinoma is similar to BCC and may involve
surgical excision, destructive therapy, or medical
therapy. Factors that influence the method
selected are tumor size, location, and extent of
invasion of neighboring structures, as well as patient
age, general health, preference, and cosmetic
requirements. Because SCC is more aggressive
than BCC, wider excisional margins are necessary
for local control.
Wide local excision with precise margin control
is a surgical option. As with BCC, all margins must
be free of tumor prior to closure of the wound. In
95% of cases well differentiated lesions <2 cm in
diameter can be adequately excised with a 4-mm
margin.187 Larger tumors require 10-mm margins.188
Recurrence rates of SCC after surgical excision
with precise margin control are 5% to 6%.189
Cottel119 argues that wider surgical margins are
necessary to achieve higher surgical cure rates (Fig
13). As tumor size increases, the likelihood of cure
diminishes because the margins needed to guaran-
tee complete excision become excessively wide.
According to Cottel,119 if the treatment of a 3-cm
tumor is to have 95% chance of success, the surgi-
cal margin must be 3.5 cm; for only a 75% chance
of cure, a 1.7-cm surgical margin is sufficient.
20
Fig 13. Margins and Cure Rates in Primary SCC by Size. (Data
from Cottel WI, unpublished, 1992.)
Treatment by Mohs micrographic technique is
also appropriate. Mohs190 reported 94% cure in
primary cutaneous SCC, and Cottel’s success is
even slightly higher (95%).119 Advantages of the
Mohs technique include tissue preservation and
lower recurrence rates. Disadvantages, as outlined
above, include patient inconvenience and expense.
Destructive techniques such as cryosurgery and
electrodesiccation and curettage do not produce
a surgical specimen for histologic and margin analy-
sis. Additionally, healing is by secondary intention,
which results in poorer scars than if the wound is
closed primarily. In short, destructive techniques
are best reserved for small, superficial lesions in
noncritical locations. The local failure rate is high,
particularly with SCC.
Of all the medical interventions available for treat-
ment of squamous cell carcinoma of the skin, only
radiation therapy is efficacious as a first-line thera-
peutic technique. Although the cure rate for pri-
mary radiotherapy in cutaneous SCC is 90%,191 the
side effects, particularly dermatitis and fibrosis, can
be unpleasant, and treatment is protracted. Thus
radiation therapy is best reserved for the debili-
tated patient who is a poor surgical candidate or
for the patient who refuses surgical intervention.189
Radiation therapy is also an effective adjuvant in
the treatment of high-stage large tumors or recur-
rent tumors requiring multimodality therapy.
Topical 5-FU is an excellent modality to treat
premalignant lesions associated with SCC (ie, AK),
but is not recommended for the primary treatment
of squamous carcinoma.

Another medical modality that has met with some
success is systemic chemotherapy, which has gen-
erally been used as an adjuvant in the management
of large tumors and in metastatic disease.192,193
Because SCC has such a high metastatic poten-
tial, a lymph node exam is mandatory. The risk of
metastasis for lesions of the trunk or extremities
ranges from 2% to 5%. Lesions of the face or
dorsum of the hand have a higher metastatic rate,
between 10% and 20%. Overall, the incidence of
regional lymphatic spread from cutaneous SCC is
less than that of mucosal SCC but greater than that
of BCC.189 Clinical lymphadenopathy with biopsy-
proven metastatic disease mandates a lym-
phadenectomy.187,194 Patients with metastatic dis-
ease may undergo multimodality therapy following
lymphadenectomy, including radiation therapy and
systemic chemotherapy. The role of prophylactic
lymphadenectomy (before the appearance of overt
disease) is unclear.194
Recurrent Tumors
Three factors have been identified as predictors
of tumor recurrence in SCC of the skin: (1) degree
of cellular differentiation; (2) depth of tumor inva-
sion; and (3) perineural invasion by tumor.
The degree of cellular differentiation is a signifi-
cant indicator of prognosis. If the tumor is well
differentiated, 7% of adequately treated SCC recur,
whereas if the tumor is moderately differentiated,
the likelihood of recurrence is 23%, and if poorly
differentiated, 28%.195
The depth of tumor invasion to a Clark IV or V
level also increases the risk of recurrence
severalfold.195
Clinical signs of perineural invasion by a cutane-
ous SCC include paresthesias, pain, tingling, numb-
ness, and paralysis; unfortunately, perineural inva-
sion frequently exists with no symptoms whatso-
ever. It is estimated that 2.5% to 5% of all cutane-
ous SCC will spread along perineural tissues,196 but
the likelihood of perineural spread may be as high
as 10%.197
Any tumor that overlies a major nerve trunk, es-
pecially on the face, should be considered potentially
involved with tumor and thoroughly investigated.
All recurrent SCC should be considered to have
perineural invasion until proved otherwise.
SRPS Volume 9, Number 5
Metastatic Tumors
Squamous cell tumors in certain areas of the body
are especially prone to metastasis. Tumors of the
scalp,198 ears,199 nostrils,200 and extremities201–203
present a higher risk of tumor spread, while the
overall incidence of regional node metastases from
squamous cell carcinoma of the skin is only 1% to
2%. 202,204 When the primary lesion is in the
extremities, the presence of positive nodes carries
a dismal prognosis: Only 35% of patients survive 5
years despite prompt nodal dissection.202 Lesions
of special etiology (Marjolin’s ulcer)32,205,206 are also
particularly aggressive and are associated with high
rates of nodal metastases and a poor prognosis.
Rowe and associates207 reviewed the literature
of squamous cell carcinoma of the skin and lip for
the past 50 years, and from this wealth of informa-
tion they determined cure rates, incidence of local
recurrence, and metastases from the disease. For
primary SCC of the skin, the 5-year recurrence rate
after treatment with Mohs micrographic surgery
was 3.1%; curettage-electrodesiccation, 3.7%; sur-
gical excision, 8.1%; and radiotherapy, 10%. For
primary SCC of the lip, Mohs micrographic surgery
was associated with recurrence rates of 2.3% after
5 years; non-Mohs methods, 10.5%. For primary
SCC of the ear, treatment by Mohs micrographic
surgery yielded 5.3% recurrences; nonMohs meth-
ods, 18.7%. When patients with recurrent SCC of
the skin were treated by Mohs micrographic sur-
gery, the overall recurrence rate was 10%. Treat-
ment by surgical excision was associated with 23.3%
recurrences (Table 5).
Several tumor variables were noted to influence
local recurrence and metastasis in cutaneous SCC
(Table 6). Lesions <2 cm in diameter had a local
recurrence rate of 7.4% and a metastasis rate of
9.1%, while those >2 cm had a recurrence rate of
15.2% and a metastatic rate of 30.3%. With respect
to Clark levels, tumors <4 mm in depth had a 5.3%
local recurrence rate and a 6.7% rate of metastasis;
tumors >4 mm deep showed 17.2% recurrences
and 45.7% metastases. Well-differentiated lesions
had a local recurrence rate of 13.6% and 9.2%
metastases, whereas poorly differentiated lesions had
28.6% local recurrences and 33% metastases.
Tumors on sun-exposed areas were associated
with 7.9% recurrences and only 5.2% metastases.
In contrast, lesions on the ear had an 18.7% local
recurrence rate and 11% metastases. Tumors of
21
SRPS Volume 9, Number 5

TABLE 5
Local Recurrence Rates for Squamous Cell Cancers of the Skin, Ear, and Lip by Treatment
Modality and Duration of Follow-up

(Reprinted with permission from Rowe DE, Carroll RJ, and Day CL Jr: Prognostic factors for local recurrence, metastasis, and survival
rates in squamous cell carcinoma of the skin, ear, and lip. J Am Acad Dermatol 26:976, 1992.)

TABLE 6 the lip had 10.5% local recurrences and a 13.7%

Influence of Tumor Variables on Local Recurrence
and Metastasis of Squamous Cell Carcinomas
of the Skin, Ear, and Lip
incidence of metastases. There were no data avail-
able for scar carcinoma except that the metastatic
rate was 37.9%.
Lesions that had been treated previously, regard-
less of location, had a 23.3% local recurrence rate
and 30.3% metastases. Tumors with perineural
involvement treated by conventional surgical exci-
sion recurred locally 47.2% of the time and
metastases developed in 47.3%.
Regardless of tumor size, anatomic location, his-
tologic definition, or previous treatment, Mohs
micrographic surgery offered the best cure (Table
7) and lowest recurrence rates (Table 8) in this
series, even for neurotropic SCC.

SCC Variants

(Data from Rowe DE, Carroll RJ, and Day CL Jr: Prognostic
factors for local recurrence, metastasis, and survival rates in
squamous cell carcinoma of the skin, ear, and lip. J Am Acad
Dermatol 26:976, 1992.)
Marjolin Ulcer
Aurelius Cornelius Celsus, a first-century Roman
physician, is credited with the first written account
of cancer arising in an old burn scar.208 It was

22

Marjolin, however, in 1827 who first reported that
the borders of chronic wounds may undergo
malignant change.209 Since then, the term “Marjolin
ulcer” has been applied to squamous cell carci-
noma arising in chronically traumatized areas such
as burn scars, fistula tracts, and drainage tracts of
osteomyelitis.
TABLE 7
Cure Rates of Squamous Cell Carcinomas of the Skin, Ear,
and Lip Treated by Mohs and Non-Mohs Modalities
According to Size and Histologic Differentiation of Lesions
(Reprinted with permission from Rowe DE, Carroll RJ, and Day
CL Jr: Prognostic factors for local recurrence, metastasis, and
survival rates in squamous cell carcinoma of the skin, ear, and lip.
J Am Acad Dermatol 26:976, 1992.)
TABLE 8
Outcome of Neurotropic SCC of the Skin, Ear, and Lip
(Reprinted with permission from Rowe DE, Carroll RJ, and Day
CL Jr: Prognostic factors for local recurrence, metastasis, and
survival rates in squamous cell carcinoma of the skin, ear, and lip.
J Am Acad Dermatol 26:976, 1992.)
Most Marjolin ulcers arise in full-thickness burn
sites that remain ungrafted or where grafts have
failed. These scars often develop chronic and
recurrent ulcerations before undergoing malignant
transformation. The tumor typically starts at the
ulcer margin and grows slowly. Only a portion of
the ulcer becomes malignant, thus false-negative
reports on biopsy are not uncommon. Localized
pain can accompany malignant transformation.210
Squamous cell carcinoma is by far the most com-
mon malignancy to arise from burn scars, although
basal cell carcinoma, melanoma, and sarcoma have
SRPS Volume 9, Number 5
all been reported.211,212 Approximately 2% of burn
scars undergo malignant transformation over time.213
The average interim between a traumatic episode
and subsequent development of a Marjolin’s ulcer
is 32.5 years, and the latency period is inversely
proportional to the age of the patient at the time of
injury.214 That is to say, the younger the patient is at
the time of injury, the longer he or she will remain
tumor-free before the scarred site shows signs of
cancerous change.
Early diagnosis relies on clinical acumen. A high
level of suspicion must be maintained for all scars
that break down and ulcerate, and liberal biopsies
must be performed in chronic wounds. False-nega-
tive biopsies are possible given the focal nature of
the malignant transformation within a bed of chronic
ulcer, thus vigilance is mandatory.
Treatment involves complete surgical excision
of tumor with precise control of margins. Mohs
micrographic technique has been suggested as an
alternative to amputation, although data regarding
long-term recurrences are not available.215
High (>30%) metastatic rates and highly aggres-
sive recurrences are reported in Marjolin’s ulcer,
with overall 5-year survival rates of <10%.216-218
Whether this is due to late detection or to aggres-
sive tumor behavior is unclear.32,219 Regional lymph
node dissection should be performed in the face
of palpable adenopathy. Elective lymph node dis-
section for prophylaxis might be a good option in
view of the overall poor prognosis,216,220-222 although
its role remains undefined.
Bowen’s Disease
Bowen’s disease appears typically as a slowly
enlarging, erythematous patch with a fairly sharp
but irregular outline, often scalloped. The red to
tan lesion is often confused with a superficial basal
cell carcinoma, from which it can be differentiated
because it lacks the elevated, thread-like border.
Within the tumor there is superficial scaling and
small areas of crusting.223 Histologically, Bowen’s
disease is a squamous cell carcinoma in situ with
epidermal and follicular involvement. The vast
majority of lesions remain localized indefinitely, with
10% of tumors becoming invasive and then only
after a long time. Bowen’s disease of the glans
penis is called erythroplasia of Queyrat.224
23
SRPS Volume 9, Number 5
Although 5-fluorouracil is said to achieve cure
rates of 92%,225,226 the recommended treatment is
still surgical excision.227-229
Verrucous Carcinoma
Verrucous carcinomas are well-differentiated
squamous cell carcinomas capable of local inva-
sion and occasional extension into bone, but rarely
metastasis. Trauma, chronic irritation, or localized
infection is usually implicated in the etiology.230
Speculation continues regarding a possible asso-
ciation of verrucous carcinoma with the human
papillomavirus.
Verrucous carcinomas may occur anywhere on
the skin surface231 but are most common on the
palms and soles, where they are known as carci-
noma cuniculatum. On the foot, carcinoma
cuniculatum appears as a wart-like lesion that gradu-
ally enlarges. As the tumor grows, it may become
polypoid, ulcerative, or fungating, with sinus tracts
to the skin that exude a foul-smelling, greasy sub-
stance. On the buccal mucosa, verrucous carci-
noma presents as multiple polypoid masses that
coalesce to form large cauliflower lesions.
Because they are of such low-grade malignancy,
verrucous carcinomas may be mistaken for
pseudoepitheliomatous hyperplasia, and the
pathologist should be alerted to the clinical diagno-
sis. The treatment of choice is surgical excision or
Mohs micrographic surgery.230
Subungual SCC
The clinical designation of subungual epidermoid
carcinoma includes a wide spectrum of histologic
changes, from invasive squamous cell carcinoma
to squamous cell carcinoma in situ, so long as it
involves the nail bed.232 The initial manifestations
are erythema, swelling, localized pain, and nail dys-
trophy, proceeding to nodularity, ulceration, and
bleeding. Tumor growth is very slow, and the
lesions are frequently misdiagnosed as warts,
paronychia, or pyogenic infection.
Historically, the treatment for squamous cell car-
cinoma of the nail bed was amputation of the distal
phalanx, which certainly yields a high cure rate but
is now considered unnecessarily aggressive, as only
two cases of metastatic subungual SCC have ever
been reported.233,234 Unfortunately, conservative
24
forms of therapy such as 5-FU or EDC cannot be
relied upon to eradicate all tumor cells. Mikhail232
believes that Mohs micrographic surgery is well-
suited to the management of subungual SCC
because it ensures complete removal of the dis-
ease with maximum preservation of normal tissue,
digit length, and digit function.
SCC MIMICS
Keratoacanthoma
Keratoacanthoma was first described by
Hutchinson235 in 1889. Rook236,237 describes the
clinical experience with this benign skin tumor over
the last century. Solitary keratoacanthoma is more
common than multiple and usually occurs on
exposed parts of the body such as the middle of
the face, lips, and dorsum of the hands. It typically
arises as a firm, small, raised half-moon covered by
normal skin except for a central keratotic plug.
The average size of a keratoacanthoma is 1–1.5
cm, but lesions up to 5 cm in diameter have been
reported. The nodule grows rapidly for 6 to 8
weeks, at which time it usually begins to disappear
spontaneously. Resolution will continue for the
next 6 to 8 weeks until all tumor is resorbed and
the corneal plug sloughs. According to this time-
table, most lesions will have a lifecycle of 4 to 6
months, although a few may take 9 months or
more to run their course.238
A keratoacanthoma is not a malignant process,
yet it grows so rapidly that it may be mistaken for a
cancerous lesion. To aid in the diagnosis, Kern and
McCray239 list 10 histopathologic criteria to differ-
entiate between keratoacanthomas and squamous
cell carcinomas.
Despite their benign nature, most authors235,240
recommend surgical excision of keratoacanthomas
because the scar resulting from spontaneous reso-
lution of the lesion is often worse than if surgically
excised. There is also the possibility of a highly
anaplastic squamous cell carcinoma masquerading
as a keratoacanthoma. The excisional biopsy
should include the entire growth.
Pseudoepitheliomatous Hyperplasia
This condition arises in sites of chronic inflam-
mation from fungal infections, draining sinuses, fis-

tulas, and nonspecific ulcers. Clinically it may be
difficult to distinguish between pseudoepi-
theliomatous hyperplasia and a verrucous carci-
noma, 241 yet while a proliferative process,
pseudoepitheliomatous hyperplasia is completely
benign.
Bowenoid Papulosis
In 1970 Lloyd242 described a peculiar condition
he called “multicentric pigmented Bowen’s dis-
ease of the groin,” which subsequently became
known as bowenoid papulosis.243 This is a benign
dermatosis of the anogenital skin and mucous
membranes characterized by multiple, 1–3 mm,
flat-topped papules that closely resemble small
verrucae. Occasionally the small papules coa-
lesce to form fairly large plaques up to 3 cm in
diameter. Histologic features are those of an
intraepidermal squamous cell carcinoma, to include
epithelial atypia, dysplastic keratinocytes, and fre-
quent mitotic figures.244 Bowenoid papulosis
affects both sexes equally. The highest incidence
of bowenoid papulosis is during the third decade
of life but has been reported in all age groups,
although it is very rare in patients younger than
20 or older than 45.245
The oncogenic human papillomavirus (HPV)
Types 16, 18, 31, 32, 34, 39, 42, 48, and 51-54
have been implicated in the development of
bowenoid papulosis.246-248 Bowenoid papulosis
in women also seems to show some preferential
association with HPV-16.249 One report notes a
high correlation between bowenoid papulosis and
neoplasia of the uterine cervix (severe dyspla-
sia).250 This increased risk has been determined
for both primary patients as well as for women
whose sexual partners suffer from the disease.250
In another series,249 HPV-16 was detected in 63%
of intraepidermal neoplasms of the external geni-
talia.
Despite the malignant histology, the lesions
behave in a benign fashion and treatment should
be conservative. One must recognize the clinical
presentation and favorable prognosis of the dis-
ease in order to avert radical surgery. There has
been one report of squamous cell carcinoma of
the anus in an HPV-16-positive man with bowenoid
papulosis and HIV-positive serum.251
SRPS Volume 9, Number 5
Proliferating Epidermoid Cysts
In 1966 E Wilson Jones252 introduced the con-
cept of proliferating epidermoid cysts to describe
lesions that begin as subcutaneous nodules and
grow into large, elevated, nodular masses having
central ulcers. Jones believed the vast majority of
carcinomas arising from epidermoid cysts repre-
sent this entity. Histologically, proliferating epider-
moid cysts exhibit interlacing strands and lobules
of squamous epithelium; foci of atypia and prema-
ture keratinization are often seen. Individual histo-
logic fields are indistinguishable from squamous
cell carcinoma, although the clinical course of the
lesions is benign.253
Brownstein and coworkers254 reviewed 50 cases
of proliferating epidermoid cysts and found 90%
of the lesions were on the scalp and 84% of the
patients were women.
Desmoplastic Melanoma
Conley and colleagues255 in 1971 reported the
course of seven patients who suffered from a patho-
logic process they termed desmoplastic melanoma.
Since that report, approximately 60 cases have been
identified worldwide. The tumors are for the most
part amelanotic and range from a few millimeters
to 4.8 cm in diameter. Histologically desmoplastic
melanoma is characterized by spindle cells within
the dermis and marked desmoplasia. Some focus
of junctional activity can usually be found in
untreated lesions. Neurotropism or perineural
invasion is common. The gender distribution is
about equal.
Desmoplastic melanoma is often mistaken for
an undifferentiated squamous cell carcinoma or a
malignant fibrohistiocytoma. In the event of an
undifferentiated tumor with questionable features,
immunoperoxidase studies are essential to arrive
at a diagnosis and determine plan of management.
Unfortunately, the majority of lesions have extended
to Clark levels IV or V before a diagnosis is made.
OTHER SKIN TUMORS
Merkel Cell Tumor of the Skin
Merkel cell tumors arise in the dermis of elderly
individuals, are locally aggressive, and may metas-
tasize to the regional lymph nodes. The lesions
25
SRPS Volume 9, Number 5
can occur almost anywhere on the body except
the trunk.256 Merkel cell tumors were previously
called trabecular carcinomas or neuroendocrine
carcinomas. Histologically, solid sheets of cells are
separated by abundant stroma. The small baso-
philic tumor cells are uniform in size, have hyper-
chromatic nuclei, scant cytoplasm, and high mitotic
activity. The tumor fills the dermis and extends into
the subcutaneous tissue or skeletal muscle, but often
there is a narrow band of papillary dermis that is
not involved with tumor.257,258
Because this is an aggressive malignancy, wide
local excision with 3–5 cm margins is recom-
mended. Therapeutic lymph node dissection is
required with palpable adenopathy. Elective lymph
node dissection is urged if nodal patterns of spread
are predictable.
Recent evidence suggests that postoperative
radiation therapy may improve 5-year survival. Che-
motherapy is still investigational.189,259-261
Dermatofibrosarcoma Protuberans (DFSP)
This is a rare fibrohistiocytic sarcoma that mani-
fests clinically as a distinctive, raised, hard lesion
which begins as a plaque or small nodule. Most
patients are 20–40 years old.
Surgical excision with 3-cm margins and under-
lying fascia is currently recommended for treat-
ment. However, the lesions exhibit a marked pro-
pensity to recur following surgical excision,
approaching 60% in some studies.262,263 The diffi-
culty in achieving high cure rates with standard
excision is attributed to the occult extension of
tumor beneath normal appearing skin. Reports of
metastasis exist but are rare.264-266 A much higher
success rate is associated with treatment by Mohs
micrographic surgery.267,268
26
CHEMOPREVENTION
Retinoids
Vitamin A and its derivatives (retinoids) are the
best studied preventive agents. Retinoids affect
cell growth, differentiation, and apoptosis by bind-
ing nuclear receptors which, as DNA-binding tran-
scription factors, modulate the expression of cellu-
lar genes.269
Topical retinoids (trans-retinoic acid), available
as tretinoin or retin-A, are effective in treating
actinic damage. Actinic keratoses, which are pre-
malignant in nature, are reversed by the use of
topical retinoids.270-273 An additional effect of topi-
cal retinoids is the accumulation of collagen in the
skin with subsequent effacement of fine
wrinkles.274-276
Daily application of the 0.1% cream (if tolerated)
or the 0.05% cream in a heavy oil base (Renova®)
is preferred. Tretinoins are dermal irritants, and a
retinoid skin reaction consisting of redness and
peeling is not uncommon. This improves with per-
sistent use of the product. Decreasing the strength
of topical retinoid used and applying topical ste-
roids will also improve the irritation, which is a
localized hypervitaminosis A.
Systemic retinoids, available commercially as oral
13-cis-retinoic acid or isotretinoin (Accutane®), are
potent teratogens and can induce long term toxic-
ity.277,278 Several studies show an apparent reduc-
tion in the frequency of nonmelanoma skin cancer
with prolonged isotretinoin therapy.279-281
5-fluorouracil
The use of 5-FU was discussed earlier in associa-
tion with the treatment of actinic keratoses.

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SRPS Volume 9, Number 5

RECOMMENDED READING

Taylor CR, Stern RS, Leyden JJ, Gilchrest BA: Photoaging/photodamage and photoprotection. J Am Acad
Dermatol 22:1-15,1990.

Miller SJ: Biology of basal cell carcinoma (Parts I and II). J Am Acad Dermatol 24:1-13 and 161-175, 1991.

Gherardini G, Bhatia N, Stal S: Congenital syndromes associated with nonmelanoma skin cancer.
Clin Plast Surg 24(4):649, 1997.

McLean DI, Gallagher R: Sunscreens: use and misuse. Dermatol Clin 16(2):219, 1998.

Farmer KL, Goller M, Lippman SM: Prevention of nonmelanoma skin cancer. Clin Plast Surg 24:663, 1997.

Bernstein PE: Mohs ’98: single procedure Mohs’ surgery with immediate reconstruction. Otolaryngol
Head Neck Surg 120:184, 1999.

Dellon AL, DeSilva S, Connolly M, Ross A: Prediction of recurrence in incompletely excised basal cell
carcinoma. Plast Reconstr Surg 75:860, 1985.

Kwa RE, Campana K, Moy RL: Biology of cutaneous squamous cell carcinoma. J Am Acad Dermatol 26:
1-26, 1992.

Gallagher RP, Hill GB, Bajdik CD, et al: Sunlight exposure, pigmentation factors, and risk of nonmelanocytic
skin cancer. II. Squamous cell carcinoma. Arch Dermatol 131(2):164-169, 1995.

Karagas MR, Stukel TA, Greenberg ER, et al: Risk of subsequent basal cell carcinoma and squamous cell
carcinoma of the skin among patients with prior skin cancer. JAMA 267:3305-3310, 1992.

Mayer MH, Winton GB, Smith AC, et al: Microcystic adnexal carcinoma (sclerosing sweat duct
carcinoma). Plast Reconstr Surg 84(6):970-975, 1989.

Brodland DG, Zitelli JA: Surgical margins for excision of primary cutaneous squamous cell carcinoma.
J Am Acad Dermatol 27:108, 1992.

Rowe DE, Carroll RJ, Day CL: Prognostic factors for local recurrence, metastasis, and survival rates in
squamous cell carcinoma of the skin, ear, and lip: implications for treatment modality selection. J Am
Acad Dermatol 26:976, 1992.

Kirsner RS, Spencer J, Falanga V, et al: Squamous cell carcinoma arising in osteomyelitis and chronic
wounds: treatment with Mohs’ micrographic surgery vs amputation. Dermatol Surg 22:1015, 1996.

34