Ultraviolet radiation

UV exposure is the predominant cause of BCC and cutaneous SCC as evidenced by migrant studies, the correlation of incidence to latitude, and animal studies. There is, however, a difference in the type of UV exposure (see Table 108.2 ). For BCCs, intermittent intense episodes of UV exposure and sunburns at any age appear to increase risk, whereas cumulative long-term UV exposure and childhood sunburns increase the risk for developing SCCs and AKs .

Sun exposure early in life appears to have a greater influence on subsequent skin cancer risk than at a later age. For example, individuals born in countries with high ambient UV radiation such as Australia have significantly higher incidence rates of BCC and SCC as compared to those with a similar genetic background (e.g. British, northern Europeans) who migrated to these locales later in life from countries with lower ambient UV radiation .

Indoor tanning usage

Several studies have demonstrated an increased risk for the development of BCCs and SCCs in those who are exposed to artificial sources of UV radiation. Intentional tanning has been shown to increase the risk of SCC development and Karagas et al. demonstrated that any use of tanning devices was associated with odds ratios of 2.5 for SCC and 1.5 for BCC, even after adjustment for history of sunburns, sunbathing, and sun exposure. In response to these findings, many countries have passed legislation aimed at regulating indoor tanning facilities, including banning minors. Notably, Australia has actually completely banned this commercial industry .

Therapeutic UVR exposure

Individuals with psoriasis have been shown to be at increased risk for the development of keratinocyte carcinomas. While long-term follow-up of psoriasis patients who underwent UVR plus tar (Goeckerman) therapy found no increased risk, long-term PUVA therapy was associated with a significant, dose-related risk of SCC development (adjusted relative risk = 8.6 for an accumulated exposure of between 100 and 337 treatments) . With prolonged therapy, a slightly increased risk for BCC development was noted as well. In addition to the direct effects of PUVA, PUVA-induced immunosuppression may also play a role.

Ionizing radiation

Exposure to ionizing radiation leads to a threefold increased risk for BCC and SCC . The risk is in proportion to the radiation dose. Larger fractionated doses (>12–15 Gy) are thought to be necessary to induce tumor formation, so the risk with a given total dose may be less if a larger number of smaller fractionated doses are given. Most SCCs and BCCs that arise after exposure to ionizing radiation do so after a long latency period of up to several decades, with most tumors appearing ~20 years after the initial exposure.

Treatment of tinea capitis with radiation (prior to the discovery of effective systemic antifungal medications) has been linked to the development of multiple BCCs. In a study of 2224 children given X-ray therapy for tinea capitis (compared with a control group of 1380 tinea capitis patients given only topical medications), the relative risk for developing BCC of the head and neck among irradiated Caucasians was 3.6 .

Patients with BCNS are exquisitely sensitive to ionizing radiation and it should be avoided if possible (see below).

Occupational risk factors

Persons with outdoor occupations have a higher risk of developing skin cancer. Airline pilots, who are exposed to ionizing radiation at flight altitudes, have been shown to have an elevated risk for both BCC and SCC . Other occupations associated with an increased risk for NMSC include agricultural workers, sailors, locomotive engineers, and textile workers.

Chemical exposures

Multiple organic chemicals have been associated with an increased risk for the development of keratinocyte carcinomas (see Table 108.2 ). Occupational chemical exposures which can lead to skin cancer most commonly involve pesticides, asphalt, tar, and polycyclic aromatic hydrocarbons, and they typically result in SCC. The skin cancers induced by chemical exposures are usually localized as well as multiple, most often appearing on the arms .

Arsenic is a well-defined cause of SCC (see Ch. 88 ). A clue to arsenic exposure is the presence of palmoplantar arsenical keratoses. BCC has also been reported following extensive arsenic exposure. The typical latency period from exposure to tumor development is 20–40 years .

Organ transplantation

Solid organ transplant recipients have a markedly increased incidence of skin cancer, primarily SCC. The incidence of BCC in organ transplant recipients is up to 5–10 times greater than in the general population, while the incidence of SCC is 40–250 times greater. Risk factors include skin phototypes I/II, cumulative sun exposure, age at transplantation, and the degree and the length of immunosuppression.

SCC is a significant cause of morbidity and mortality in transplant recipients . The pathogenesis of skin cancer in transplant recipients is multifactorial, involving decreased immunity, direct carcinogenic effects of immunosuppressive medications, and HPV infection in addition to UVR exposure. Transplant recipients are prone to developing numerous lesions and are more likely to suffer local and regional recurrences and metastases . AKs and SCCs begin to appear with increasing frequency several years after transplantation. Lesions are often multiple and usually develop in sun-exposed areas. HPV DNA is found in approximately 70–90% of transplant-associated SCCs. Tumors from transplant recipients contain HPV strains that occur in common benign cutaneous warts (HPV types 1 and 2), EV (HPV-5 and others), high-risk oncogenic warts (HPV types 16 and 18), and low-risk oncogenic genital warts (HPV types 6 and 11). Sometimes, several HPV types are detected within a single tumor.

In one series of renal transplant patients from the US, 5% of the patients died of skin cancer. In another series of heart transplant patients from Australia, 27% died of skin cancer. Two-thirds of these deaths were due to SCC. Several studies have shown that in renal transplant patients sirolimus, an mTOR inhibitor, reduced the development of SCCs when compared to calcineurin inhibitors (e.g. cyclosporine, tacrolimus) . In an Australian study, the SCCs in those receiving sirolimus were more superficial, but this has not been observed in other studies. Based upon currently available data, sirolimus appears to be preferable in patients with a history of SCCs or strong risk factors. Unfortunately, 30–50% of renal transplant patients may not tolerate prolonged administration of sirolimus .

Patients who receive hematopoietic transplants do not experience this marked increase in skin cancer incidence (unless they have received long-term voriconazole), presumably because of a shorter duration of immunosuppression.

Immunosuppressive drugs

Use of immunosuppressive drugs, including systemic immunomodulators (“biologics”), increases the risk for the development of skin cancer . Risk of SCC development is directly related to length of immunosuppressive drug usage. In one study, the risk of SCC was significantly increased among recipients of oral glucocorticoids (odds ratio = 2.31) and the risk of BCC was also elevated (odds ratio = 1.49) . Similarly, thiopurine use for inflammatory bowel disease has been shown to increase the risk for NMSC .

HIV infection

Patients with HIV infection are at increased risk for the development of several cancers, including cutaneous SCC . The incidence of HPV-related SCC of the anus is significantly increased in this population, and can be more aggressive. For monitoring, anal cytology can be performed.

Genetic predisposition

Phenotypic characteristics such as red hair, light skin, poor ability to tan, and freckling have been identified as risk factors for melanoma as well as NMSC . Pigmentation is a polygenic trait, with polymorphisms in several genes leading to the variation observed in the human race (see Ch. 65 ). A key gene encodes the human melanocortin-1 receptor (MC1R) which is expressed on the cell surface of melanocytes. Population-based studies in diverse ethnic groups have shown that the coding region of the human MC1R is remarkably polymorphic. In Caucasians, there is a strong association between nine common MC1R variant alleles and the red hair/fair skin phenotype, thus placing these individuals at higher risk of photocarcinogenesis . Based upon genome-wide association studies and candidate gene studies (see Ch. 54 ), ~30 and at least 11 susceptibility loci for BCC and SCC, respectively, have been identified, and they include multiple pigmentation loci.

Genetic syndromes associated with an increased risk of BCCs and/or SCCs

Basal cell nevus syndrome (BCNS)

BCNS is an autosomal dominant disorder due to an inactivating mutation in PTCH1 or rarely PTCH2 . Manifestations of the syndrome include multiple or early-onset BCCs, odontogenic keratocysts of the jaw, palmoplantar pits, calcification of the falx cerebri, and skeletal anomalies ( Table 108.3 ; Fig. 108.1 ). Affected individuals may develop specific neoplasms such as medulloblastomas, meningiomas, (bilateral) ovarian fibromas, and cardiac fibromas. Of note, the medulloblastomas usually arise during early childhood, so suspicion of BCNS at an early age allows screening of at-risk individuals .

Table 108.3

Diagnostic criteria for basal cell nevus syndrome (BCNS).

The diagnosis of BCNS requires two major or one major and two minor criteria . BCC, basal cell carcinoma.

Adapted from .

DIAGNOSTIC CRITERIA FOR BASAL CELL NEVUS SYNDROME (BCNS)

Major criteria

1. More than two BCCs or one BCC before the age of 20 years 2. Odontogenic keratocysts of the jaw (proven by histology) 3. Three or more palmar or plantar pits 4. Bilamellar calcification of the falx cerebri 5. Bifid, fused or markedly splayed ribs 6. First-degree relative with BCNS

Minor criteria

1. Macrocephaly (determined after adjustment for height) 2. Congenital malformations: cleft lip or palate; frontal bossing; “coarse face”; moderate or severe hypertelorism 3. Other skeletal abnormalities: Sprengel deformity * ; marked pectus deformity; marked syndactyly of the digits 4. Radiographic abnormalities: bridging of the sella turcica; vertebral anomalies such as hemivertebrae and fusion or elongation of the vertebral bodies; modeling defects of the hands and feet; flame-shaped lucencies of the hands or feet 5. Bilateral ovarian fibromas 6. Medulloblastoma

 

* Unilateral elevation of smaller-sized scapula.

Basal cell nevus syndrome.

A Numerous small and several large nodular BCCs on the face. B Multiple palmar pits.

B, Courtesy, Jeffrey P Callen, MD.

BCCs usually appear after puberty, but they may develop during childhood. The number of BCCs in a single patient varies from a few to more than a thousand and the size from pinpoint to >5 cm (see Fig. 108.1A ). The BCCs favor the sun-exposed areas of the face, neck and upper trunk, but may occur in sun-protected sites. As in the general population, nodular BCCs usually occur on the face, while superficial BCCs are found primarily on the torso. Individual lesions may be papulonodular, pedunculated, pigmented, eroded, ulcerated, or have a combination of these features. The pigmented BCCs are sometimes misdiagnosed clinically as melanocytic nevi (see Fig. 108.21 ). The clinical course of the cutaneous tumors is usually indolent prior to puberty, after which they enlarge and eventually ulcerate, as in the general population. Individuals with BCNS are exquisitely sensitive to ionizing radiation, and hundreds of tumors can develop in children within radiation ports following radiotherapy for medulloblastoma. Additional cutaneous findings include epidermoid (infundibular) cysts and facial milia.

Actinic keratosis

Actinic keratoses (AKs) were initially described as solar keratoses (due to their suspected cause) and senile keratoses (due to the age of onset). The term “actinic keratosis” is preferred over solar keratosis, partly because the abbreviation SK also stands for seborrheic keratosis.

AKs have historically been characterized as being “precancerous” or “premalignant” because the atypical keratinocytes within these lesions are confined to the epidermis. There is no risk of metastasis until these lesions evolve into invasive carcinoma. The likelihood of an invasive SCC evolving from a given AK has been estimated to occur at a rate of 0.075–0.096% per lesion per year. Additional estimates of progression to invasive SCC range from 0 to 0.6% per year; the latter figure was derived from an elderly population with a history of keratinocyte carcinoma .

AKs are among the most frequently encountered skin lesions in clinical practice. They present on sun-damaged skin of the head, neck, upper trunk, and extremities ( Fig. 108.2A ). Individuals at higher risk of developing AKs include the elderly, those with lighter skin phototypes and those with a history of chronic sun exposure. The primary lesion is a rough erythematous papule with white to yellow scale. Patients may report tenderness. AKs can range in size from a few millimeters to large confluent patches several centimeters in diameter, especially in patients with severe photodamage. One of the earliest signs is slight erythema with almost imperceptible scale ( Fig. 108.2B ), although some lesions are devoid of visible erythema and present only as slight scale with indistinct borders. A clue to their presence is background photodamage, i.e. dyspigmentation, telangiectasia and solar elastosis (see Ch. 87 ). Advanced lesions are typically thicker and well-defined with more visible hyperkeratosis and erythema. Lesions typically are clustered in areas of highest cumulative sun exposure, such as the superior helices of the ears, upper forehead, supraorbital ridge, nasal bridge, malar eminences, dorsal hands, extensor forearms, shins, and the bald scalp ( Fig. 108.2C ). Of note, clinically, AKs may spontaneously regress, but then can reappear in the same site .

Actinic keratoses (AKs).

A Multiple AKs on the face of an elderly woman with fair complexion, blue eyes, and moderate to severe photodamage; the AKs vary in size from a few millimeters to over a centimeter. On the left forehead, the red nodule with slight scale-crust represents a well-differentiated SCC. B Pink-colored atrophic AK with minimal scale on the forehead. C Multiple AKs on the bald scalp, some of which are hyperkeratotic; the area of hypopigmentation represents a site of previous treatment and due to the field defect, recurrence at the edge is commonly observed. D Multiple, large hypertrophic AKs on the shin of an elderly woman; note the thick scale.

B, Courtesy, Iris Zalaudek, MD; D, Courtesy, Jean L Bolognia, MD.

Visual inspection is best performed with simultaneous palpation to detect lesions that may not be readily apparent. This is especially true in individuals with significant background erythema from chronic sun exposure or rosacea. Tenderness on palpation should alert the clinician to the possibility that the lesion has evolved into carcinoma. Clinical subtypes of AKs include the classic variant already described, hypertrophic (or hyperkeratotic), pigmented, lichenoid, atrophic, bowenoid, and actinic cheilitis.

Hypertrophic (hyperkeratotic) AKs are easily identified on visual inspection as papules and plaques with scale or scale-crust and an erythematous base ( Fig. 108.2D ). The erythematous base often extends beyond the overlying hyperkeratosis. The hyperkeratotic scale can become white or yellow–brown over time. Due to their thickness, patients often find these lesions to be bothersome. Sometimes distinction from SCC can be difficult and biopsy is warranted. Occasionally, hyperkeratotic AKs may develop cutaneous horns which manifest as columns of thick cornified material that protrude above the skin. These should be biopsied to exclude the possibility of an underlying malignancy, as ~15% of cutaneous horns have invasive SCC at their bases .

Pigmented AKs, sometimes called superficial pigmented AKs (SPAKs), represent a subtype that often lacks associated erythema and has a hyperpigmented or reticulated appearance ( Fig. 108.3 ). These lesions can at times be difficult to distinguish from reticulated seborrheic keratoses, lentigines, or even the lentigo maligna subtype of cutaneous melanoma. Dermoscopy may be a useful adjunct in these situations. Clinical clues are the location on sun-exposed skin, background solar changes, and hyperkeratosis that is sometimes appreciable by palpation. In cases in which the diagnosis is questionable, a biopsy is required to exclude the possibility of melanoma.

Pigmented actinic keratoses.

A,B The hyperpigmentation can have a reticulated appearance and there may be associated scale but an absence of erythema.

Courtesy, Kalman Watsky, MD.

Lichenoid AK is characterized histopathologically by the presence of a dense band-like inflammatory infiltrate. Clinically, this lesion is similar to the classic form of AK but has more erythema surrounding the base of the lesion. Patients may relate pruritus or tenderness that coincides with the onset of the lichenoid infiltrate in a pre-existing AK. It may be confused with a related lesion, the lichen planus-like keratosis, which also arises within areas of sun-damaged skin and can be pruritic, multiple, and eruptive .

Atrophic AKs usually have minimal surface change but are appreciated as pink to red, slightly scaly macules or patches (see Fig. 108.2B ) that are found by histopathologic examination to have an atrophic epidermis.

Actinic cheilitis is the term used to describe the characteristic changes that occur on the lower vermilion lip of individuals with moderate to severe photodamage. Actinic cheilitis may resemble the classic form of AK, with well-demarcated, erythematous papules or thin plaques with scale. In other patients, the erythema and especially the scale is more diffuse and can involve the entire lower vermilion lip; areas of leukoplakia may also be present ( Fig. 108.4 ). When clinical distinction between actinic cheilitis and SCC of the lip is not possible, a biopsy should be performed. The potential for evolving into invasive SCC is higher for actinic cheilitis than it is for classic AKs.

Actinic cheilitis.

Erythema and scale of the entire lower vermilion lip with erosions and areas of leukoplakia.

Courtesy, Kalman Watsky, MD.

Squamous cell carcinoma in situ

SCC in situ is commonly called Bowen disease ( Fig. 108.5 ). The most common presentation of SCC in situ is an erythematous scaly patch or slightly elevated plaque that often arises within sun-exposed skin of an elderly individual. However, it can develop in younger individuals with significant photodamage or in sun-protected sites. Bowen disease may arise de novo or from a pre-existing AK. The head and neck, followed by the extremities and trunk, are the most common sites. Lesions can become crusted and in SCC in situ of anogenital mucosa, erosions may be prominent ( Fig. 108.6 ).

Squamous cell carcinomas in situ , Bowen disease type.

A Scaly red plaque on the chest with skip areas and background photodamage. B Larger broken-up pink plaque with scale-crust in the pubic region, a sun-protected site. This type of lesion is often misdiagnosed as dermatitis or psoriasis and treated with topical corticosteroids. C Bright red, well-demarcated plaque on the proximal nail fold with associated horizontal nail ridging; the possibility of HPV infection needs to be considered. D Dermoscopic findings of tiny dotted vessels in the upper half of the lesion combined with superficial scales. E Extensive involvement of the finger which was misdiagnosed clinically as an inflammatory dermatosis and treated for years with corticosteroid creams.

B, Courtesy Kalman Watsky, MD; D, Courtesy, Iris Zalaudek, MD.

Squamous cell carcinoma in situ , erythroplasia of Queyrat type.

Large, eroded erythematous plaque with well-demarcated borders. The lesion began on the shaft of the penis.

Clinical distinction of SCC in situ from AK, superficial BCC, psoriasis, or chronic eczema may at times be difficult (see Fig. 108.5B,E ). Generally, AKs are smaller lesions and superficial BCCs often have a more translucent quality with slight elevation of the leading edge as well as characteristic dermoscopic features (see Ch. 0 ). Patients with psoriasis and diffuse actinic damage can pose a diagnostic dilemma, as concomitant psoriatic papules and plaques may clinically resemble AKs and Bowen disease.

Arsenic-induced SCC in situ resembles the classic variety clinically but has a marked tendency to be multifocal and to arise in sun-protected areas of the trunk. Associated findings include palmoplantar keratoses and guttate hypopigmentation superimposed on hyperpigmentation (see Ch. 88 ).

Bowenoid papulosis is a term used when histopathologic changes of SCC in situ are found within genital warts, usually due to infection with an oncogenic strain such as HPV-16 or -18. Dermatologists often prefer to use this term when multiple papules are present, as opposed to calling all of them SCC in situ , because the lesions rarely become invasive. The clinical appearance can vary from small brown papules of the penis to perianal pink papules to corrugated pink to brown plaques of the inguinal creases (see Chs 73 & 79 ). Whether this entity represents true SCC in situ , or is a histopathologic simulant, is a matter of debate.

Other variants of SCC in situ include a pigmented variant often seen in individuals with darker skin types and a verrucous form. Pigmented SCC in situ may be mistaken for a pigmented AK or even a superficial melanoma and verrucous SCC in situ may simulate a seborrheic keratosis or a wart clinically.

Invasive cutaneous squamous cell carcinoma

Invasive cutaneous SCC usually arises within a background of sun-damaged skin, most commonly on the bald scalp, face, neck, extensor forearms, dorsal hands, and shins ( Fig. 108.7A,B ). The color usually varies from erythematous to skin-colored; rarely there are pigmented variants. SCCs are often papulonodular, but can be plaque-like, papillomatous, or exophytic. The degree of associated scale varies, with some lesions becoming quite hyperkeratotic; other secondary changes include crusting, erosions, and ulcerations ( Fig. 108.7C,D ).

Clinical spectrum of cutaneous squamous cell carcinoma (SCC).

A Eroded and keratotic nodule that developed rapidly at the site of trauma on the shin. B Large, fungating nodule on the dorsum of the hand. C Multiple eroded superficial SCCs in association with actinic damage and sites of previous treatment on the cheek and neck of an elderly man. D Eroded, slightly vegetating, thick plaque arising within lichen sclerosis of the vulva.

A, Courtesy, Jean L Bolognia, MD.

The natural history of SCCs also varies, from slowly enlarging to rapidly growing with significant tenderness and even pain. Of note, paresthesias, anesthesia and pain may be signs of perineural invasion. The clinical differential diagnosis, in addition to hypertrophic AK, is outlined in Table 108.4 .

Staging of SCC takes into account tumor volume as measured by diameter (<2 cm vs ≥2 cm) and depth of invasion (>2 mm), and SCCs arising within sun-damaged skin are often early stage, i.e. T1/AJCC Stage I ( Table 108.5 ). Anatomic sites with a greater risk of aggressive biologic behavior include the ear , the lips ( Fig. 108.8 ), and mucosal sites including the vulva and penis (see Fig. 108.7D ). Clinical examination of patients with invasive SCC includes palpation of regional lymph nodes for enlargement and firmness, followed by assessment of size if enlarged.

Squamous cell carcinoma (SCC) of the lower lip.

A Extensive hyperkeratosis and leukoplakia of the lower vermilion lip; histopathologically, the SCC was superficially invasive and well-differentiated. B Verrucous and eroded nodule on the lower vermilion lip in a heavy smoker.

Keratoacanthoma

Keratoacanthomas (KAs) are considered by some to be a variant of SCC and by others to represent benign tumors (i.e. pseudomalignancy). The exact nosology is still uncertain, although there are some data that support its differentiation from “conventional” SCC. Typically, a rapidly enlarging papule evolves into a sharply circumscribed, crateriform nodule with a keratotic core over a period of a few weeks ( Fig. 108.9A,B ), and then it may resolve slowly over months to leave an atrophic scar . Most lesions occur on the head and neck or in sun-exposed areas of the extremities, with or without symptoms of pain or tenderness.

Clinical spectrum of keratoacanthomas.

A , B Rapidly growing, erythematous crateriform nodules with a rolled border and central keratotic core . C Progressive peripheral expansion and central involution with residual atrophy characterize keratoacanthoma centrifugum marginatum. D Giant keratoacanthoma with a yellow–red color and a history of rapid growth.

There are several distinct clinical presentations of KA, including solitary, multiple, grouped, keratoacanthoma centrifugum marginatum ( Fig. 108.9C ), giant ( Fig. 108.9D ), subungual, palmoplantar, intraoral, multiple spontaneously regressing (Ferguson–Smith), multiple non-regressing, and generalized eruptive (Grzybowski). KAs are also seen in patients with Muir–Torre syndrome and they may have sebaceous differentiation (see Ch. 63 ). In addition, multiple KAs have been associated with chemical exposures, immunosuppression , BRAF inhibitors, and HPV infection .

By far the most common presentation is the solitary KA. While most of these tumors are small (5 to 15 mm), some KAs (e.g. keratoacanthoma centrifugum marginatum [see Fig. 108.9D ]) may reach several centimeters in diameter, persist for months before resolution, and heal with prominent scarring. Grouped KAs may resolve more slowly than solitary KAs, while subungual KAs have been associated with underlying bony destruction.

The Ferguson–Smith syndrome is an autosomal dominant condition due to mutations in TGFBR1 which encodes TGF-β receptor type 1. Multiple KAs develop within sun-exposed areas, usually beginning during the third decade of life. Lesions typically regress over weeks to months, but rare examples of metastases have been reported.

Multiple KAs of the Grzybowski type present as thousands of papules resembling milia or early eruptive xanthomas. They develop rapidly and may slowly resolve over a period of months . Patients often have scarring, ectropion, and a mask-like facies.

Verrucous carcinoma

Verrucous carcinoma is a rare, well-differentiated variant of SCC which tends to occur in middle-aged and older adults. It is considered a low-grade malignancy with three major subtypes: (1) epithelioma cuniculatum (plantar surface of the foot); (2) giant condyloma acuminatum of the genitalia (also known as Buschke–Löwenstein tumor; see Ch. 79 ); and (3) oral florid papillomatosis (oral mucosa). Of note, the “cuniculatum” refers to the rabbit burrow-like appearance with crevices.

Clinically, verrucous carcinomas present as large (sometimes huge), exophytic tumors with a papillomatous or verrucous surface ( Fig. 108.10A,B ). They are commonly associated with HPV infection, and distinguishing between a verrucous carcinoma and a large wart or condyloma acuminatum can be difficult. Gradual penetration of verrucous carcinomas into underlying tissues can result in destruction of subcutis, fascia, and bone. These tumors can arise within scars and amputation stumps ( Fig. 108.10C ) as well as in association with osteomyelitis fistulae and chronic venous insufficiency. Verrucous carcinomas often recur after attempted removal, but they usually do not metastasize, except for recurrent or irradiated tumors with anaplastic transformation.

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