Chapter 114 :: Squamous Cell Carcinoma

entity caused by inflammatory, vascular, or traumatic factors.

Histopathologically, it almost always displays either findings of SCC in situ or
focal areas of invasive SCC, and thus is considered a precancerous lesion at best
and always warrants treatment. Erythroplakia can involve any mucosal surface
but most commonly occurs on the oral mucosa in more than half of all cases. Of
all oral precancerous lesions, it is considered to be the most dangerous and
carries the greatest risk of progressing to or harboring invasive carcinoma.
EPIDEMIOLOGY
Erythroplakia is an uncommon lesion in the oral cavity, and it is said to be one of
the least commonly diagnosed lesions among the group of oral lesions that may
or may not become malignant.216 The prevalence, based on a small number of
worldwide studies, is between 0.02% and 0.83%.217 Both tobacco and alcohol
are considered etiologic factors, and it mainly occurs in middle-aged individuals
without a gender preference. It has been well described in the chutta smokers
(reverse cigar smokers) of India.217
CLINICAL FINDINGS
OE is usually found either intraorally or on the vermillion surface of the lower lip.
The most common areas in the oral cavity are the soft palate, the floor of the
mouth, and the buccal mucosa. OE usually presents as a solitary, subtle,
asymptomatic, erythematous macule or patch. Most often it is less than 1.5 cm
in its widest diameter, but lesions up to 4 cm in diameter have been
described.217 Characteristically, it is sharply demarcated from the surrounding
pink mucosa, and its surface is most often smooth and homogeneous in color. On
occasion lesions of erythroplakia demonstrate a pebbled or stippled surface
change and on palpation may have a soft and velvety feel. Induration indicates
the presence of invasive carcinoma in many instances. Erythroplakia is
commonly seen in association with leukoplakia, a condition termed
erythroleukoplakia. It is the red patches of erythroleukoplakia that are most likely
to contain or develop into a malignancy.
KEY REFERENCES
Full reference list available at www.DIGM8.com
DVD contains references and additional content
14. Salasche SJ: Epidemiology of actinic keratoses and squamous
cell carcinoma. J Am Acad Dermatol 42:S4, 2000
20. Grossman D, Leffell DJ: The molecular basis of nonmelanoma
skin cancer. Arch Dermatol 133:1263, 1997
29. Thompson SC et al: Reduction of solar keratoses by regular

sunscreen use. N Engl J Med 329:1147, 1993

46. Drake LA et al: Guidelines for the care of actinic keratoses.
J Am Acad Dermatol 32:95, 1995
58. Korman N et al: Dosing with 5% imiquimod cream three
times per week for the treatment of actinic keratosis: Results
of two phase 3, randomized, double-blind, parallel-group,
vehicle-controlled trials. Arch Dermatol 141:467, 2005
69. Lawrence N et al: A comparison of the efficacy and safety
of Jessners solution and 35% trichloroacetic acid vs 5%
fluorouracil in the treatment of widespread facial actinic
keratoses. Arch Dermatol 131:176, 1995
79. Piacquadio DJ et al: Photodynamic therapy with ALA topical
solution and visible blue light in the treatment of multiple
actinic keratoses of the face and scalp: Investigator-blinded,
phase 3, multicenter trials. Arch Dermatol 140:41, 2004
110. Schwartz RA: Arsenic and the skin. Int J Dermatol 36:241,
1997
143. Novick M et al: Burn scar carcinoma: A review and analysis
of 46 cases. J Trauma 17:809, 1977
164. Meyer T et al: Importance of human papillomaviruses
for the development of skin cancer. Cancer Detect Prev
25:533, 2001
195. Reibel J: Prognosis of oral premalignant lesions: Significance
of clinical, histopathological and molecular biological
characteristics. Crit Rev Oral Biol Med 14:47, 2003
Chapter 114 :: Squamous Cell Carcinoma
:: Douglas Grossman & David J. Leffell
Cutaneous squamous cell carcinomas (SCCs) are malignant neoplasms derived
from suprabasal epidermal keratinocytes. These and basal cell cancers are the

nonmelanoma skin cancers that represent the most common malignancies in

humans. Whereas basal cell carcinoma (BCC) (see Chapter 115) is thought to
arise de novo, SCC probably evolves in most cases from precursor lesions of
actinic keratosis (AK) and Bowen disease (SCC in situ) (see Chapter 113). This
chapter focuses on clinical aspects of invasive SCC. Cutaneous SCC represents a
broad spectrum of disease ranging from easily managed, superficially invasive
cancers to highly infiltrative, metastasizing tumors that can result in death. The
clinical presentation can be variable despite the existence of easily identified
typical
SQUAMOUS CELL CARCINOMA
AT A GLANCE
With basal cell carcinoma, most common human malignancy.
Diagnosis is by biopsy.
Caused by ultraviolet radiation in most cases.
Precursor lesion is actinic keratosis.
Treatment options are excision, Mohs
micrographic surgery, and radiation.

1284
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Section 21 :: Epidermal and Appendageal Tumors lesions. The cellular and
molecular aspects of SCC carcinogenesis are discussed elsewhere (see Chapter
113).
HISTORICAL ASPECTS
EPIDEMIOLOGY
INCIDENCE. The precise incidence of BCC and SCC is unknown, because these
cutaneous malignancies are not generally documented by the National Cancer
Institute or most state cancer registries. However, it is generally accepted that
well over 1 million cases are diagnosed in the United States each year, with
approximately 200,000 representing SCC.10 Although less common than BCC,
SCC carries a risk of metastasis and thus accounts for the majority of the several
thousand deaths attributable to nonmelanoma skin cancer each year. By
comparison, cutaneous melanoma accounts for only 60,000 cases, but
approximately 9,000 deaths, annually.11 Similar trends for SCC have been noted
in Australia12 and the Caribbean.13
SCC is strongly associated with advanced age, and a sharp increase in incidence
is seen after age 40 years.14 Today, the lifetime risk of SCC among whites is
approximately 15%, almost double that of two decades ago. Increased exposures
to ultraviolet (UV) radiation (through greater use of tanning salons, increased
time spent outdoors, changes in clothing styles, and ozone depletion) and
greater longevity have been suggested as possible causes for the increase in
disease. It is likely that this trend will continue as a result of further depletion of
the ozone layer and the aging of the US population. The rising incidence of SCC
over the past several decades has been paralleled by a 20% decrease in
mortality, attributed largely to increased public awareness and aggressive
treatment of high-risk lesions.15 After a diagnosis of SCC, patients have a 44%
50% cumulative risk of developing another nonmelanoma skin cancer (18%30%
risk of SCC) in the subsequent 35 years.16 In addition, these patients are at
increased risk for extracutaneouscancers.17
DEMOGRAPHICS
Squamous cell cancer is twice as common in men as in women, probably as a
result of greater lifetime UV exposure in men. Similarly, longer hairstyles and use
of lipstick may account for the lower frequency of SCC on the ears and lips of
women. There is an inverse relationship between skin pigmentation and SCC
incidence, largely because of the protective effect of eumelanin. Thus, persons
with white skin, blue eyes, fair complexion, red hair, and Celtic ancestry who tan
poorly are at greatest risk. Increased pigmentation is associated not only with a
lower incidence of SCC, but also with an inversion in the BCC/SCC ratio. In

comparison with whites, the incidence of SCC is decreased by 30-fold in

American blacks and the BCC/SCC ratio falls to 0.8:1.14 Tanzanian albinos all
develop SCC by young adulthood, and the ratio of BCC to SCC is only 0.2:1.
Asians and Polynesians, with intermediate skin pigmentation, have
correspondingly intermediate levels of SCC. A gene (MC1R) involved in
melanogenesis that encodes the melanocortin 1 receptor is a major determinant
of skin pigmentation and hair color. The MC1R gene is highly polymorphic, with
more than 20 variants described.18 Several variant MC1R alleles are associated
with increased risk of SCC that is independent of skin type and hair color.
ETIOLOGY AND PATHOGENESIS
PREDISPOSING FACTORS
There are a number of factors, including both acquired and genetic skin
conditions that may predispose to SCC (Table 114-1). Patients often demonstrate
a multiplicityof factors that together are sufficient to induce SCC development.
For example, a given skin site may be exposed to both UV radiation and another
environmental carcinogen.
PRECURSOR LESIONS. Most SCCs develop from precursor lesions such as AKs or
Bowen disease (see Chapter 113).
ULTRAVIOLET RADIATION EXPOSURE.
UV radiation is considered the predominant risk factor for SCC. Importantly, there
is a linear correlation between the incidence of SCC and exposure to UV
radiation. The incidence of SCC has been reported to double with each 810
decline in geographic latitude and is highest at the equator.19 World War II
veterans stationed in the Pacific developed much higher rates of SCC than did
their colleagues who served in Europe.20 Similarly, SCC is more prevalent in
Japanese people who emigrated to Hawaii than in those who remained in
Japan.21 Excessive UV radiation appears to be related more to the development
of SCC than to the development of BCC. Rates of SCC rise more rapidly than
those of BCC with increasing UV exposure,22 and UV radiation-induced skin
cancers in mice are almost exclusively SCCs rather than BCCs.23 Moreover, in
patients receiving long-term therapy with psoralen plus ultraviolet A (UVA)
radiation for treatment of
TABLE 114-1
Predisposing Factors for Squamous Cell
Carcinoma
Precursor lesions (actinic keratosis, Bowen disease)
Ultraviolet radiation exposure
Ionizing radiation exposure

Exposure to environmental carcinogens

Immunosuppression
Scars
Burns or long-term heat exposure
Chronic scarring or inflammatory dermatoses
Human papillomavirus infection
Genodermatoses (albinism, xeroderma pigmentosum,
porokeratosis, epidermolysis bullosa)

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Chapter 114 :: Squamous Cell Carcinoma
psoriasis there is an associated 30-fold increase in nonmelanoma skin cancers,
most of which are SCCs.24
IONIZING RADIATION.
There is a strong association between SCC and exposure to ionizing radiation. In
one survey of SCC patients, an association with radiation therapy was observed
only in those whose skin was likely to sunburn (see Chapter 113).
ENVIRONMENTAL CARCINOGENS.
Numerous occupational and environmental carcinogens, such as arsenic and
aromatic hydrocarbons, predispose to the development of SCCs. With the
exception of 3-methylcholanthrene and anthramine, chemical carcinogens
generally produce SCCs rather than BCCs.25 Exposures to insecticides and
herbicides have also been associated with SCCs. In addition, smoking and alcohol
use are strongly associated with SCCs of the oral cavity.
IMMUNOSUPPRESSION.
Chronic immunosuppression may lead to an increase in SCCs, primarily on sunexposed sites.26 An 18-fold increase in SCC has been reported in renal
transplant patients27; these tend to appear 37 years after the onset of longterm immunosuppressive therapy, with corticosteroids, azathioprine, and
cyclosporine most frequently implicated. With the increase in the total number of
organ transplant patients, management of SCCs in this population is becoming
more important. In patients with leukemia and lymphoma, SCCs are both
increased and more aggressive.28 Although multiple SCCs have been described
in patients infected with human immunodeficiency virus, advanced human
immunodeficiency virus infection has generally not been associated with an
increased incidence of SCC, possibly because many patients do not live long
enough to develop them.
SCARS AND UNDERLYING DISEASES.
Historically, SCC was associated with both burn scars and chronic ulcers as noted
earlier, but such associations are seldom seen today. Also rare but reported is the
development of SCCs in the context of chronic infections, particularly those
associated with draining sinuses and scarring, such as perianal pyoderma,
osteomyelitis, chromomycosis, hyalohyphomycosis, granuloma inguinale, lupus
vulgaris, and leprosy. Chronic inflammatory processes, particularly those
associated with scarring, such as venous ulcer, snakebite ulcer, discoid lupus
erythematosus, oral lichen planus, morphea, lichen sclerosus, pilonidal cyst,

acne conglobata, hidradenitis suppurativa, HaileyHailey disease, dissecting

folliculitis of the scalp, and necrobiosis lipoidica, all can give rise to SCCs. An
exception is vaccination scars, which are associated with BCCs rather than SCCs.
SCCs have also been observed in transplanted skin, epidermal cyst, dental cyst,
and dermoid cyst.

THERMAL FACTORS.
Long-term heat exposure can lead to SCCs. The role of thermal radiation in the
development of skin cancer has long been recognized in many cultures, where
common practices include placing hot ashes under the clothes to keep warm in
winter or smoking opium while lying on heated beds. The incidence of SCCs is
increased in persons who habitually sit in front of heating stoves and at sites of
erythema ab igne (see Chapter 113).
VIRAL INFECTION.
A role for human papillomavirus (HPV) infection has been well established in
some types of SCCs. Verrucous carcinoma appears to be associated with several
HPV types, as noted later. Head and neck and periungual SCCs are frequently
associated with HPV-16. Patients with epidermodysplasia verruciformis are
chronically infected with HPV, most commonly type 5, and one-third of these
patients ultimately develop SCCs (see Chapters 113 and 196). Recently, the
MCPyV polyoma virus, originally discovered in Merkel cell carcinoma, was
identified in approximately 15% of cutaneous SCCs from immunocompetent
patients.A An etiological role for MCPyV in SCC remains to be demonstrated.
GENODERMATOSES.
A variety of heritable diseases predispose to SCC development. Patients with
oculocutaneous albinism develop predominantly SCCs (rather than BCCs) at an
early age (see Chapter 73). Xeroderma pigmentosum (see Chapters 110 and
139), a disorder of DNA repair, is also characterized by early development of
SCCs. SCCs have been reported to develop in the Mibelli, disseminated
superficial actinic, and palmaris et plantaris disseminata forms of porokeratosis
(see Chapter 52), and in oral lesions of dyskeratosis congenita. As noted in
Section Viral Infection, lesions of epidermodysplasia verruciformis can
degenerate into SCCs (see Chapter 196). Finally, patients with the dystrophic
form of epidermolysis bullosa are at increased risk for SCC (see Chapter 62).
MOLECULAR ASPECTS
As in most cancers, the development of SCC from normal keratinocytes begins
with mutations in the cellular DNA and genomic instability. Alterations in gene
expression lead to loss of growth controls, penetration of the basement
membrane, and ultimately invasion into surrounding tissue. Along the pathway
to SCC, keratinocytes become resistant to apoptosis (programed cell death) and
immune attack.

GENETIC ALTERATIONS.
Most analyses of genetic alterations in SCCs have been performed in cases of
oral or head and neck SCCs. Chromosomal deletions (loss of heterozygosity)
commonly involve chromosomes 3, 9, 11, and 17; the regions most commonly
identified include 9p21 and 17p13 where the INK4A (p16/Arf) and p53 tumor
suppressors, respectively, are located.29 Similar genetic lesions were found in a
study of young patients (younger than 40 years of age).30 It is unclear whether
these genetic markers will serve as useful prognostic indicators.
p53 IN THE DEFENSE AGAINST SKIN CANCER.
A role for p53, cyclin D1, human telomerase reverse transcriptase, p16, and
thrombospondin has been identified in the multistep process of human skin
Carcinogenesis.31
Apoptosis of keratinocytes that have sustained UV radiation-induced DNA
damage, termed sunburn cells, requires the p53 tumor suppressor and
represents a key protective mechanism against skin cancer by removing
premalignant cells that have acquired mutations. In keratinocytes, UV radiation
upregulates p53,32 which delays cell cycle progression until DNA damage can be
repaired or facilitates cell elimination by apoptosis.33 Compromise of p53
function could undermine this apoptosis-based defense mechanism, giving
UVdamaged cells a selective advantage to survive additional cycles of UV
exposure.34 Further impairment of p53 and other genes through additional UV
radiation-induced mutations may then lead to even greater resistance to
apoptosis, increased proliferation, and ultimately development of SCC. The
increased susceptibility of p53-deficient mice to UV radiation-induced SCC35
highlights this protective role of p53.
p53 MUTATIONS IN SQUAMOUS CELL CARCINOMA.
Consistent with the scenario described in Section p53 in the Defense Against
Skin Cancer, mutations in the p53 gene are a common finding in SCC.36 In most
cases, these are C.T single base and CC.TT tandem transition mutations at
dipyrimidine sequences, i.e., UVB-signature mutations.37 Most SCCs exhibit
loss of heterozygosity with respect to p53 and isolated mutations on the
remaining allele. In one study, the p53-apoptosis pathway was disrupted in 50%
of oral SCCs. With respect to SCC precursors, p53 mutations were found in up to
75% of AK and SCC in situ lesions.38 Interestingly, although different p53
mutations were found in separate AKs, all cells within a single precursor lesion
had the same mutation.31 Mutations in p53 can also be detected in
keratinocytes from clinically normal sun-exposed skin.39 Keratinocytes with p53
mutations occur in clonal patches that are larger and more frequently in sunexposed skin.40 These findings substantiate a clonal basis for UV radiation
induced SCC and suggest that p53 mutation is an early event in the development
of SCC. In addition to undergoing mutation, p53 can be compromised in
keratinocytes infected with HPV. The E6 protein encoded by oncogenic HPV types
binds p53 and targets it for rapid degradation, which disables the p53-apoptosis

pathway. This is a primary mechanism by which HPV infection predisposes to SCC

(see Chapter 196).
OTHER APOPTOTIC REGULATORS IN SQUAMOUS CELL CARCINOMA.
In addition to dysregulation of p53, dysregulation of other apoptotic regulatory
proteins has been described in SCC. In a study of vulvar SCC, expression of the
apoptotic inhibitor Bcl-2 correlated with metastasis.41 Similarly, in esophageal
SCC, expression of the apoptotic inhibitor Bcl-XL correlated with tumor invasion
and metastasis.42 In SCC of the tongue, low apoptotic index and decreased
expression of the proapoptotic Bcl-2-associated X protein (Bax) correlated
significantly with poor prognosis, whereas low Bcl-2 expression was associated
with a favorable clinical outcome.43 Expression of the antiapoptotic Bcl-2associated athanogene 1 (BAG-1) was associated with nodal metastasis in oral
SCC.44 Consistent with these observations, transgenic mice expressing Bcl-2 and
Bcl-XL in the skin exhibit increased susceptibility to chemical-induced
tumorigenesis. In addition to these Bcl-2 family members, the inhibitor of
apoptosis protein survivin is expressed in both SCC and precursor lesions,45 and
in one study its expression correlated with aggressive tumor phenotype.46
Interestingly, survivin may be negatively regulated by the binding of p53 to its
promoter.47 More recent studies in transgenic mice have yielded paradoxical
results, which suggests that apoptosis may be required in the initial phase of UV
radiation-induced clonal expansion.48
IMMUNE EVASION.
Working with UV radiationinduced SCCs in mice, Kripke and colleagues first
demonstrated the importance of immunosuppression in UV radiation-induced
SCC in the 1970s (see Chapter 90). They found that although UV radiationinduced SCC was promptly rejected when transplanted into genetically identical
recipient mice, the transplanted tumors grew rapidly, and rejection did not occur
if recipient mice were first treated with a subcarcinogenic dose of UV radiation.
These experiments suggested that UV radiation not only induced SCC but also
impaired the ability of host animals to mount protective immune responses
against foreign tumor antigens.
CLINICAL FINDINGS
In white men and women, the majority of SCCs arise on sun-exposed areas such
as the head, neck, and dorsal hands. SCC of the legs is more common in
women.49 On the other hand, in blacks SCCs tend to be distributed equally on
sun-protected and sun-exposed areas.50 SCC typically presents in solitary
fashion, arising from precursor lesions as noted earlier. An exception is in
immunosuppressed patients, who may manifest eruptive SCCs.
DEVELOPMENT FROM PRECURSOR
LESIONS
(See Chapter 113)

AKs often occur as a multiplicity of lesions, ranging in size from pinpoint to over 2
cm, and the borders are usually ill defined. A dry adherent scale gives them
rough, gritty texture. By contrast, lesions of Bowen disease are usually solitary,
sharply demarcated, scaling papules or plaques, often initially mistaken for
eczema, psoriasis, or lichen simplex. The latter disorders are often pruritic,
whereas Bowen disease is usually not. In sun-protected sites, Bowen disease
may have a noneczematous appearance. For example, it may appear verrucous
in the anogenital area, nail bed, and eyelid, and as a dark patch or oozing
erythematous plaque in intertriginous areas. These precursor lesions are usually
asymptomatic, and the development of tenderness, induration, erosion,
increased scale, or enlarging diameter may herald evolution into SCC. Typically, a
patient with multiple AKs may present with a single lesion that gradually
becomes more prominent than the rest (Fig. 114-1), or with a solitary, persistent,
nonpruritic, scaling patch that is unresponsive to treatment with topical steroids.
SQUAMOUS CELL CARCINOMA
MORPHOLOGIES
A firm, flesh-colored or erythematous, keratotic papule or plaque is most
common (see Fig. 114-1), but SCCs may also be pigmented. Other presentations
include as an ulcer (Fig. 114-2), a smooth nodule (Fig. 114-3), or a thick
cutaneous horn. SCC may also be verrucous or present as an abscess,
particularly if in a periungual location (see Fig. 113-9 in Chapter 113). The
margins may be indistinct. With enlargement, there is usually increased firmness
and elevation. Progressive tumor invasion ultimately results in fixation to
underlying tissues. Especially in the head and neck region, an enlarged lymph
node nearby that is firm and nontender may indicate tumor metastasis
(Fig. 114-4).
ORAL SQUAMOUS CELL CARCINOMA
SCC of the oral cavity usually occurs in patients with a long history of cigarette
smoking, tobacco chewing, or alcohol use, but it has now been documented in
younger adults without these traditional risk factors.
Figure 114-1 Papular squamous cell carcinoma (SCC) of the ear.
The differential diagnosis includes chondrodermatitis nodularis helicis, which,
unlike SCC, is associated with pain.
Figure 114-2 Ulcerative squamous cell carcinoma of the jaw. In this region,
extension of the cancer can invade themarginal mandibular nerve.
Figure 114-3 Nodular squamous cell carcinoma of the forehead. This lesion is
recurrent and can be seen arising in the previous surgical scar. It should be
considered high risk.
There is a male predominance, and the palate and tongue are the most common
sites. Oral SCC most commonly evolves from lesions of erythroplakia and is

usually asymptomatic (see Chapter 113). Distinct patterns include a persistent

rough red patch or granular velvety red plaque that ultimately becomes firm and
nodular. Surprisingly, the risk of transformation to SCC does not appear to
correlate with the degree of epithelial dysplasia.51 The floor of the mouth,
ventrolateral tongue, and soft palate are considered high-risk sites. It may also
present as a peritonsillar abscess.

Figure 114-4 Preauricular mass resulting from metastasis of cutaneous squamous

cell carcinoma (SCC). Involvement of the parotid gland can result from
metastasis of SCC in the temple and ear region.
Figure 114-5 Squamous cell carcinoma of the lower lip that developed in the
setting of habitual sun exposure and actinic cheilitis. There is a large but subtle
nodule, better felt than seen, on the lower lip. There are areas of hyperkeratosis
and ulceration. Metastasis to draining lymph nodes can occur.
Figure 114-6 Perianal squamous cell carcinoma (SCC) in situ. Identification of
these lesions requires thorough proctoscopic examination and monitoring for
invasive SCC.
LOWER LIP SQUAMOUS CELL
CARCINOMA
SCC of the lower lip begins as a roughened papule of actinic cheilitis or scaly
leukoplakia, with slow progression to a tumor nodule (Fig. 114-5). Clinical clues
associated with evolving SCC include persistent lip chapping with localized scale
or crust, red and white blotchy atrophic vermilion zone of the lip, indistinct or
wandering vermilion border, and small fissuring or ulceration within an area of
indurated actinic cheilitis. Symptoms of underlying pain or altered sensation
should be investigated as a potential sign of perineural invasion.
GENITAL SQUAMOUS CELL
CARCINOMA
SCC of the vulva most commonly occurs on the anterior labia majora, beginning
as a small warty nodule or an erosive erythematosus plaque. These lesions may
be asymptomatic but more often are associated with pruritus or bleeding.
Lesions of lichen sclerosus are another common precursor of SCC of the vulva.
SCC of the cervix is associated with HPV infection, most commonly with type 16.
SCC of the scrotum begins as a small pruritic verrucous lesion that becomes
friable with increasing size. SCC of the penis usually occurs in uncircumcised
males (see eFig. 114-5.1 in online edition) and, although very uncommon in
Western countries, may account for 10% of cancers in places where genital
hygiene is poor. A distinct precursor of penile SCC is erythroplasia of Queyrat
(see Chapter 113), characterized by a velvety red plaque. In addition to lack of
circumcision, penile SCC has been associated with a history of condyloma and
phimosis and lichen sclerosus et atrophicus (see Chapters 65 and 78). The
genitalia were once thought to be a common location for SCC after long-term
therapy with psoralen and UVA radiation, but this complication can be avoided by
shielding the genitalia during treatment, and such an association is rarely seen
today. Perianal SCC may also occur (Fig. 114-6).

Figure 114-7 Verrucous carcinoma presenting as a thick plaque arising on the

buccal mucosa. This type of tumor was formerly called oral florid papillomatosis.
Figure 114-8 Epithelioma cuniculatum, verrucous carcinoma of the foot.
SCAR SQUAMOUS CELL CARCINOMA
SCCs arising in scars typically begin decades after injury, with skin breakdown
and persistent erosion. Most commonly this occurs on the lower extremities at
sites of chronic pyogenic or venous stasis ulcers. Gradually nodularity develops,
although detection is often delayed because of concealment by surrounding
indurated scar tissue. However, when SCC arises in chronic sinuses nodularity
may not be present. The development of increased pain, drainage, or bleeding
alone should raise concern and warrants further investigation.
KERATOACANTHOMA
(For Full Discussion, See Chapter 117)
The hallmark of keratoacanthoma is rapid growth, up to several centimeters in
weeks, and then gradual involution over a period of months in most cases (see
Chapter 117). The typical presentation is in an elderly patient on a sun-exposed
site, particularly an extremity. Morphologically, keratoacanthoma is usually a
large, smooth, dome-shaped, verrucous nodule with a central keratotic crater.
Although historically viewed as a benign neoplasm because of its tendency
toward spontaneous resolution, keratoacanthoma can be locally destructive and
aggressive and must be viewed as a clinical subtype of SCC. This tumor may
occur in association with sebaceous neoplasms and gastrointestinal malignancies
in MuirTorre syndrome.
VERRUCOUS CARCINOMA
Verrucous carcinoma is a form of SCC that encompasses several clinical entities,
all characterized by slow-growing exophytic tumors with a cauliflower-like
appearance that develop at sites of chronic irritation.52 They may be clinically
mistaken for giant warts. Four subtypes are recognized based on site of
occurrence. Type I consists of oral tumors on the buccal mucosa of elderly male
tobacco chewers and has been referred to as oral florid papillomatosis (Fig. 1147). Representing 2%12% of all oral cancers, these tumors are most commonly
found on the buccal mucosa, tongue, gingiva, and floor of the mouth. Type II is
the anogenital type, as described by Buschke and Loewenstein. It occurs on the
glans penis of young uncircumcised males, on the scrotum, on the perianal
region in both sexes, and, less commonly, on the female genitalia. Type III, also
known as epithelioma cuniculatum, is a malodorous tumor often found on the
plantar area in elderly men (Fig. 114-8) It usually involves the skin underlying the
first metatarsal head and tends to form draining sinuses that are caniculated
(like rabbit burrows) in appearance. Finally, type IV occurs at other sites,
including the scalp, trunk, and extremities. Detection of sequences from HPV

types 6, 11, 16, and 18 in epithelioma cuniculatum and type 11 sequences in

oral verrucous carcinoma raises the possibility that these tumors evolve from
verruca vulgaris.

METASTATIC SQUAMOUS CELL CARCINOMA

Metastatic SCC in the skin can have a variety of presentations. It may be
signaled by a palpable lymph node near the site of treatment of a previous SCC.
On the other hand, it may present as large keratotic papules or nodules
resembling the primary lesion (Fig. 114-9). Metastatic SCC on the skin may be
the first sign of internal malignancy, initially presenting in the skin as clusters of
firm pink or red papules that may be keratotic centrally.

HISTOPATHOLOGY GENERAL CONSIDERATIONS

The hallmark of invasive SCC is the extension of atypical keratinocytes beyond
the basement membrane and into the dermis (Fig. 114-10). The absence of a
connection between tumor cells and the epidermis should raise concern for
metastatic SCC, although this may simply reflect undermining from adjacent
tumor. In every case, it is important to note clues that may indicate a precursor
lesion or particular etiology. For example, the presence of solar elastosis and
keratinocyte atypia at the margins would suggest that the SCC is actinically
derived. On the other hand, the presence of scar tissue may indicate recurrent
disease or a sinister scar-associated SCC. These considerations have important
implications for treatment and prognosis, as discussed in Section Treatment.
BASIC FEATURES
The tumor may appear as single cells, small groups or nests of cells, or a single
mass. The inferior border may broadly impose on the dermis or be represented
by individual foci of microinvasion. Invasive tumor is usually confined to the
dermis and subcutaneous involvement is unusual. There are typically varying
proportions of normal-appearing and atypical squamous cells, the latter
characterized by increased mitoses, aberrant mitotic figures, nuclear
hyperchromasia, and loss of intercellular bridges. Squamous differentiation is
seen as foci of keratinization in concentric rings of squamous cells called horn
pearls. Loss of differentiation is associated with decreased keratin production.
GRADING
Histologic grading of SCC is based on the degree of cellular differentiation. Lowgrade tumors are comprised of uniform cells, resembling mature keratinocytes,
with intracellular bridges and keratin production. By contrast, high-grade SCCs
are characterized by atypical cells, loss of intracellular bridges, and minimal or
absent keratin production. Another feature of higher grade tumors is a less
distinct demarcation between malignant cells and adjacent normal stroma. In
1932, Broders53 introduced a formal grading system based on keratinocyte
differentiation that is still used today. Tumors are graded on a scale of 14 based
on increasing percentages of undifferentiated cells (Table 114-2). In addition to
grade, the depth of penetration, tumor thickness, and hair follicle involvement
should also be reported.
HISTOLOGIC SUBTYPES
There are many histologic subtypes of SCC.54 In the adenoid (or
pseudoglandular) SCC, there is a tubular microscopic pattern and keratinocyte
acantholysis. In clear cell SCC, the keratinocytes appear clear as a result of
hydropic cytoplasmic swelling and accumulation of lipid vacuoles. Spindle cell
SCC reveals spindle-shaped atypical cells. Signet-ring cell SCC is
Figure 114-9 Squamous cell carcinoma metastatic to skin.

Figure 114-10 Squamous cell carcinoma demonstrating invasive cancer with

atypical keratinocytes and foci of keratinization.

TABLE 114-2
Broders Grading System for Squamous Cell Carcinoma
Grade % Undifferentiated cells Other features
1 <25 Keratinization
2 <50
3 <75
4 >75 Atypia, loss of
intracellular bridges

a rare variant characterized by concentric rings composed of keratin and large

vacuoles corresponding to markedly dilated endoplasmic reticulum. In addition, a
basaloid variant has been described. In verrucous carcinoma, the superficial
component resembles verruca vulgaris with prominent acanthosis and
papillomatosis, whereas the deeper component extends downward, displacing
collagen bundles. Finally, keratoacanthoma reveals a symmetric keratin-filled
crater, with the epidermis on each side extending over to form a distinct lip.
DIAGNOSIS AND DIFFERENTIAL
DIAGNOSIS
DETERMINATION OF THE DIAGNOSIS
The diagnosis of SCC is always made by skin biopsy. Any persistent, enlarging, or
nonhealing lesion, particularly if on a sun-exposed site, warrants biopsy
evaluation. It is important that the biopsy be of sufficient depth so that invasive
SCC can be distinguished from in situ disease. If a lesion is flat or minimally
elevated (less than 1 mm), the superficial shaving technique can be used to
minimize wound size and scarring and is usually adequate. For elevated lesions,
the punch technique or a deep shave excision should be used to ensure that a
specimen of adequate depth is taken. Because the diagnosis of keratoacanthoma
depends largely on overall architecture, performing excisional biopsy or taking
an incisional ellipse through the entire lesion is recommended. A tangential
excision through the deep dermis also usually suffices.
DIFFERENTIAL DIAGNOSIS
Clinically, the differential diagnosis of SCC is long, but it can be narrowed based
on lesion morphology. For verrucous or scaly lesions, benign conditions to
consider include wart, seborrheic keratosis, AK, melanocytic nevus, pyogenic
granuloma, eccrine poroma, and deep fungal infections such as chromomycosis.
The entity erosive pustular dermatosis of the scalp is a benign condition that is
often initially mistaken for SCC but responds to potent topical steroids.55 Other
malignant verrucous lesions include atypical fibroxanthoma, BCC, Bowen
disease, verrucous melanoma, Merkel cell carcinoma, and, of course, metastatic
SCC. Pigmented SCC in particular may mimic melanoma. For ulcerative lesions,
additional diagnoses include trauma, BCC, and herpes virus infection (with either
herpes simplex virus or varicella-zoster virus). Histologically, the differential
diagnosis of welldifferentiated SCC includes verruca vulgaris and inverted
follicular keratosis. In addition, reactive epidermal hyperplasia
(pseudoepitheliomatous hyperplasia) secondary to mycosis, eruptions in
response to halogenated drugs (bromoderma and iododerma), and even
mechanical trauma can mimic SCC. However, in these hyperplasias the
keratinocytes usually remain well differentiated; the margins of the proliferating
epidermis are often pointed or irregular, rather than bulbous; there is leukocyte
invasion with occasional keratinocyte disintegration; and granulomas or

intraepidermal abscesses may be present.56 Some adenoid SCCs may

demonstrate a pseudovascular pattern, with erythrocytes in pseudovascular
spaces, and may be confused with angiosarcoma; these tumors do not express
factor VIII antigens or bind ulex agglutinin. Clear cell SCC may simulate adnexal
tumors with sebaceous differentiation or sebaceous carcinoma. Distinguishing
spindle cell SCC from atypical fibroxanthoma is difficult. The differential diagnosis
of poorly differentiated SCC also includes fibrosarcoma, Merkel cell carcinoma,
and melanoma. In most cases, SCC can be distinguished from these others by
special stains for various cytokeratins, but in difficult cases electron microscopy
may be needed to establish the diagnosis. In general, SCC does not stain for
melanocyte (S100 protein, homatropine methylbromide) or smooth muscle
(vimentin, actin) markers.
RECURRENCE AND METASTASIS
SCC, like BCC, may cause local tissue destruction, but it also has significant
potential for metastasis. Metastases, when they occur, are generally to regional
lymph nodes and are detected 13 years after initial diagnosis and treatment.19
In many cases, metastasis is preceded by local recurrence at the site of the
primary lesion. Historically, the reported rate of metastasis for SCC has ranged
from 0.5% to 6%,57 and metastasis tends to occur with tumors that are large,
recurrent, and involve deep structures or cutaneous nerves (Fig. 114-11).
HIGH-RISK LESIONS
In a classic study, Rowe et al58 reviewed all major series of SCC dating back to
1940 to determine risk factors associated with recurrence and metastasis. Table
114-3 summarizes the characteristics of high-risk lesions. With respect to size,
tumors smaller than 2 cm in diameter are low risk, with an overall metastatic
rate of roughly 1%. In one study,59 the metastatic rate increased to 9.2% and
14.3% for tumors of 25 cm and larger than 5 cm, respectively. With respect to
depth and invasion, tumors less than 4-mm deep and rated as Clark levels IIII
have limited metastatic potential,
TABLE 114-3
High-Risk Squamous Cell Carcinoma
Diameter >2 cm
Depth >4 mm and Clark level IV or V
Tumor involvement of bone, muscle, nerve Location on ear, lip Tumor arising in
scar Broders grade 3 or 4 Patient immunosuppression Absence of inflammatory
infiltrate

whereas close to half of those deeper than 4 mm and at Clark levels IV or V were
metastatic in some series. Tumor involvement of bone, nerve, or muscle tissue is
strongly associated with metastasis. With respect to anatomic site, SCC of the
ear has the highest rate of recurrence (18.7%), whereas lip SCC has the highest
rate of metastasis (13.7%), with half of lip metastases present at the time of
initial diagnosis. All SCCs arising in scars are high risk, with metastatic rates
approaching 40% in some series.60 By contrast, SCCs arising in actinically
damaged skin are of considerably lower risk, with an average metastatic rate of
5.2%. Poorly differentiated SCCs (Broders grade 3 or 4) demonstrate a
recurrence rate of 28.6% and a metastatic rate of 32.8%, compared with 13.6%
and 9.2%, respectively, for well-differentiated tumors. The prognosis is
particularly poor for spindle cell SCCs.61 Immune status is another important
consideration. One study62 found that 23% of patients with metastatic SCC were
immunosuppressed. A heavy inflammatory response appears to be a favorable
prognostic sign, because absence of infiltrate has been correlated with higher
rates of recurrence and metastasis.
TREATMENT
Box 114-1 summarizes the various modalities available for treatment of SCCs.
Treatment selection is directed largely by assessment of tumor risk for
recurrence and metastasis, as discussed in the previous section. Ablative
techniques such as electrodesiccation and curettage, liquid nitrogen cryotherapy,
carbon dioxide laser, intralesional chemotherapy, and photodynamic therapy are
superficial, do not allow histologic margin control, and thus are generally
inappropriate for treatment of invasive SCCs. Topical chemo/immuno therapy
may be appropriate for SCC in situ, and topical 5-fluorouracil has been used for
treatment of conjunctival SCCs.63
SURGICAL EXCISION
Conventional surgical excision is viewed by many as treatment of choice for
small primary SCCs. Recommended margins are 4 mm for low-risk lesions or
SCCs with a depth of less than 2 mm; for lesions with a depth of more than 6 mm
or a diameter larger than 1 cm, Mohs micrographic surgery is recommended.64
Mohs micrographic surgery is also recommended in specific circumstances when
the highest cure rate and minimal tissue destruction are desired (Table 114-4).
Specifically, tumors involving the periocular or periauricularareas; recurrent or
large tumors; lesions with poorly defined clinical margins; tumors at sites where
tissue preservation is important (nasal tip, lip, eyelid, ear, genitalia); deeply
infiltrative tumors; lesions A B
Figure 114-11 A. Infiltrative squamous cell carcinoma (SCC) demonstrating
retraction of underlying tissue of the left

cheek, where extension might involve infraorbital nerve. B. SCC of left side of
forehead, where extension to bone with invasion or along the supraoptic nerves
might lead to death.
Box 114-1 Treatment of Squamous Cel Carcinoma
Nonexcisional ablative techniques (in situ disease
only, or in special circumstances)
Mohs micrographic surgery
Conventional surgical excision
Topical therapy (in situ disease only)
Radiation therapy

at sites that were previously irradiated; tumors with involvement of underlying

structures (nerve, bone, muscle); tumors in immunosuppressed patients; and
lesions at sites associated with high recurrence rates should strongly be
considered for Mohs micrographic surgery.65 Additional indications include
verrucous carcinomas and high-risk SCCs such as those arising from chronic
scarring conditions.
RADIATION
Radiation can be used to treat superficially invasive to moderate-risk lesions and
serves as an important adjuvant to excisional surgery in treating residual
microscopic disease and providing prophylaxis against metastatic disease. It has
been shown to be particularly useful for SCCs of the external auditory canal,66
although radiation therapy may lead to hearing loss.67 Radiation therapy is not
advised for verrucous carcinoma, in which there is an associated low rate of
anaplastic transformation. Radiation may also be used as adjuvant therapy in
cases in which perineural SCC was identified in surgical pathologic specimens
but treatment failures occurred.
TOPICAL THERAPY
Both topical 5-fluorouracil and imiquimod have been used in patients with SCC in
situ Practice varies, but most regimens consist of application either once or twice
daily for 24 weeks (5-fluorouracil) or three to five times per week for 24
months (imiquimod). Recent evidence suggests that efficacy of imiquimod may
be due to enhanced interferon-. production and effector function of T cells
infiltrating the tumor.B Topical therapy is not appropriate for invasive disease
since there will be minimal penetration of drug into the dermis.
RECURRENCE RATES
Many risk factors for recurrence and metastasis have been identified.9 In their
review noted in Section High- Risk Lesions, Rowe et al58 also assessed
responses to treatment. They reported increasing combined rates of recurrence
for each of the following treatment modalities (for primary cancers): Mohs
micrographic surgery (3.1%), electrodesiccation and curettage (3.7%), excisional
surgery (8.1%), and radiation (10%). A review of the use of Mohs micrographic
surgery to treat SCC with 4-year follow-up reported a cure rate of 92%.68 The
surprisingly low rate of recurrence for electrodesiccation and curettage likely
reflects its judicious use for treatment of low-risk lesions. Similarly, the
recurrence rates for both Mohs micrographic surgery and excisional surgery may
be somewhat skewed by their use in treating high-risk lesions. A systematic
review of studies using topical therapy for SCC in situ (with at least 6 months
histologic follow-up) revealed clearance rates of 27%85% with 5-fluorouracil and
73%88% with imiquimod.C For lip SCC, the overall recurrence rate was 2.3%
with Mohs micrographic surgery compared with 10.5% with other treatment
modalities; for ear SCC, the recurrence rates were 5.3% and 18.7%, respectively.

For all recurrent tumors, cure rates were 76.7% with excision, compared with
90% with Mohsmicrographic surgery. For low-risk SCCs, overall recurrence rates
were 1.9% with Mohs micrographic surgery versus 16.5% with all other
modalities. Overall 5-year survival rate for patients with metastatic SCCs was
26.8%, with poorer outcomes among patients with lip lesions69 and those
treated with surgery alone (and no radiation).
TREATMENT OF HIGH-RISK LESIONS
Management of high-risk lesions is reviewed elsewhere.70 Oral 5-fluorouracil has
been used to treat aggressive lesions refractory to conventional therapies.
Additional treatments, including -carotene, interferon, and retinoids, have been
employed with variable results. High-risk lesions may require formal staging.
Computed tomography or magnetic resonance imaging may be useful in the
detection of advanced perineural involvement of head and neck SCC.71 Sentinel
lymphadenectomy has been combined with Mohs micrographic surgery.72
Involvement of lymph nodes may warrant radical lymph node dissection and
radiation therapy. Elective cervical lymphadenectomy may be indicated for highrisk lesions of the lip.73 When a clinical lymph node examination yields negative
results, further intervention may still be indicated if the tumor is considered
sufficiently high risk.
PATIENT FOLLOW-UP
After a diagnosis of SCC, all patients should be considered at high risk for
developing additional lesions of SCC as well as BCC. They should be seen at
regular intervals, ranging from 3 months to 12 months, depending on the degree
of risk of prior lesions, status of precursor lesions, and individual patient
compliance. A complete skin examination should be performed at each visit,
including examination of the oral mucosa. In addition, sites of previous lesions
and treatments should be assessed for signs of recurrence. Finally, a lymph node
examination is indicated to monitor for metastatic disease.
TABLE 114-4
Indications for Mohs Micrographic Surgery
Infiltrative squamous cell carcinoma (SCC)
Poorly defined clinical margins
Location on lip, ear, nail bed, nasal tip, eyelid, genitalia
History of radiation at site
Involvement of nerve, bone, muscle
Immunosuppressed patient
Recurrence of large SCC
Verrucous carcinoma

SCC arising from chronic scarring conditions

PREVENTION
Those at risk for SCCnamely, persons with a prior history of nonmelanoma skin
cancer or any of the predisposing conditions discussed earliershould be
monitored closely. They should receive complete skin examinations on a regular
(annual or semiannual) basis.
SUN PROTECTION
The most effective preventive measure is protection from sun exposure. It is
likely that adequate sun protection beginning in early childhood could prevent
most SCCs.74 This requires establishing patterns of behavior at an early age,
such as applying sunscreen repeatedly, wearing hats and protective clothing,
and avoiding the sun during the hours of peak intensity. However, the
importance of sun exposure prevention in childhood should not be construed to
mean that sun protection later in life will be of no benefit. There is evidence that
aggressive sun protection throughout life can prevent the development of SCC
precursor lesions and cancers themselves.
TREATMENT OF PRECURSOR LESIONS
Treatment of precursor lesions is expected to reduce the incidence of SCC.
Several options are available for treatment of AK (see Chapter 113). Isolated
lesions can often be effectively removed by liquid nitrogen cryotherapy. For
patients with many AKs or areas of skin with a multitude or confluence of lesions,
topical chemotherapy using 5-fluorouracil or imiquimod is a better option. Topical
diclofenac has also been introduced as therapy for widespread AK. Photodynamic
therapy using aminolevulinic acid is also an option for areas involving multiple
lesions.
OTHER PREVENTIVE MEASURES
A number of additional preventive measures can be taken that may reduce the
incidence of SCC in individual patients. For example, the use of condoms can
prevent transmission of HPV and may thereby reduce the risk of genital SCC.
Decreased alcohol consumption and smoking cessation is likely to reduce the risk
of oral SCC. Several years ago there was great interest in the use of both
retinoids and interferons as systemic chemopreventive agents. Low-dose
etretinate (10 mg/ day) has been used successfully in renal transplant
patients.75 A more recent recommendation is isotretinoin (Accutane; 10 mg
every day or every other day) in addition to topically applied tretinoin.76 The
introduction of a vaccine for the prevention of infection with HPVs and of
precancerous lesions of the cervix may one day translate into the prevention of
all HPVinduced precancerous lesions of the skin.78
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Full reference list available at www.DIGM8.com

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