Chapter 114. Squamous Cell Carcinoma

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 lesions. The cellular and molecular aspects of SCC carcinogenesis are discussed elsewhere (see Chapter 113).

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 3–5 years.16 In addition, these patients are at increased risk for extracutaneous–cancers.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.

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 multiplicity of 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 8°–10° 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 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 sun-exposed sites.26 An 18-fold increase in SCC has been reported in renal transplant patients27; these tend to appear 3–7 years after the onset of long-term 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, Hailey–Hailey 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 1 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 UV-damaged 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 sun-exposed 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-2-associated 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 radiation-induced 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 radiation-induced 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 a 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. 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.

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) 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).

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 Muir–Torre 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. 114-7). 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.

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. Low-grade 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 1–4 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 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.

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 well-differentiated 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.

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 1–3 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 2–5 cm and larger than 5 cm, respectively. With respect to depth and invasion, tumors less than 4-mm deep and rated as Clark levels I–III have limited metastatic potential, 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.

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 the 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 periauricular areas; 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 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 2–4 weeks (5-fluorouracil) or three to five times per week for 2–4 months (imiquimod). Recent evidence suggests that efficacy of imiquimod may be due to enhanced interferon-γ 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 Mohs micrographic 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 β-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 high-risk 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.

Those at risk for SCC—namely, persons with a prior history of nonmelanoma skin cancer or any of the predisposing conditions discussed earlier—should 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 HPV-induced precancerous lesions of the skin.78