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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.
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Most SCCs develop from precursor lesions such as AKs or Bowen disease (see Chapter 113).
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Ultraviolet Radiation Exposure
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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
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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).
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Environmental Carcinogens
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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.
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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.
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Scars and Underlying Diseases
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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.
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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).
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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.
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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).
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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.
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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.
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p53 in the Defense Against Skin Cancer
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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
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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.
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p53 Mutations in Squamous Cell Carcinoma
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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.
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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).
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Other Apoptotic Regulators in Squamous Cell Carcinoma
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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
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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.
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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.
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Development from Precursor Lesions
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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.
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Squamous Cell Carcinoma Morphologies
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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).
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Oral Squamous Cell Carcinoma
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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.
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Lower Lip Squamous Cell Carcinoma
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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.
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Genital Squamous Cell Carcinoma
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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).
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Scar Squamous Cell Carcinoma
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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.
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(For Full Discussion, See Chapter 117)
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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.
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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.
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Metastatic Squamous Cell Carcinoma
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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.
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