Lower extremity (LE) SCCs arise in the context of multiple etiologies. While there is no single pathologic event that leads to SCC, particularly in the setting of LE ulcers, de novo disease is likely the cumulative effect of multiple risk factors. The incidence of SCC increases with age [26, 27]. Rates of disease are at least 5–10 times higher in patients over 75 and some studies estimate a 50–300 times higher prevalence compared to those under the age of 45 [20, 28, 29]. Gender differences are fairly consistent worldwide, with higher SCC rates in men than in women. LE SCCs occur much more commonly in women [30–32], a finding which may be partially explained by clothing and lifestyle [33].

Although less common in darker-skinned ethnic groups, SCC in these populations is associated with greater morbidity and mortality. In Africans, East Asians, and South Asians, SCC frequently occurs in areas of chronic injury or inflammation, including chronic leg ulcers, burn scars, skin infections, or sites of irritation from tight clothing [34–37]. There is a propensity for SCC to occur on the lower extremities in these populations, a site that also tends to be the most common location of repeated cutaneous injury. In particular, the anterior surface of the LE is more prone to trauma, and SCCs tend to occur on the front of the leg [38].

Because of the stark difference of SCC presentation in darker-pigmented persons, ultraviolet radiation is not believed to play an equally important etiologic role [7]. Darker-skinned groups are believed to receive photoprotection from increased melanocyte activity and larger, more dispersed melanosomes [39, 40]. Compared to light-skinned individuals, it is estimated that a 30-fold higher dose of ultraviolet radiation (UVR) is required to produce even minimally perceptible erythema and skin damage [41].

However it remains evident that LE SCCs, like SCCs in general, are in part related to sunlight exposure [41, 33]. UVR from the sun is thought to be the most important environmental exposure responsible for SCC [8, 31]. Both lifetime and occupational sun exposure have been linked to SCC [30, 42]. Additionally, the anterior surface of the leg may receive more sun exposure than the rest of the leg, resulting in 10–17 % higher rates in this area [43]. This causal etiology of UVR is further substantiated by evidence supporting the efficacy of daily sunscreen use in reducing the incidence of SCC [44].

Other forms of radiation have also been linked to SCC. Psoralen followed by exposure to UVA radiation, a combination known as PUVA used to treat a variety of dermatoses, increases the risk for developing squamous cell carcinoma as much as 35-fold [45–48]. Tanning beds, which primarily emit UVA radiation, have been implicated by multiple studies including a recent meta-analysis [49–52]. Therapeutic ionizing radiation, grenz rays, and gamma rays are all associated with the development of SCC [53].

SCC occurs more frequently in patients who are immunosuppressed after solid organ transplants [54–58] and disease tends to be more aggressive than in the immunocompetent [59, 60]. Immunosuppressive agents are believed to augment UVR-related damage both directly [61] and through decreased immune surveillance [57], leading to an increased risk of multiple and recurrent lesions [62].

As previously mentioned, there is an increased risk of cutaneous SCC in chronically inflamed skin resulting from scars, burns, chronic ulcers, sinus tracts, or inflammation. It is estimated that 2 % of all SCCs arise within chronic scars and a staggering 95 % of all skin cancers arising in chronically inflamed skin are SCCs [63, 64]. Chronic inflammation is a particularly important risk factor in patients with dark-pigmented skin and thought to be responsible for almost half of SCC in this population [7].

SCCs arising in ulcers, also known as Marjolin’s ulcers, occur more often in men. There is wide variation between the initial skin injury and appearance of malignancy, with reports of SCC appearing as early as 6 weeks or as late as 50 years after the traumatic event [65–67]. Mortality rate rises with increasing latency, and LE SCCs have a worse prognosis [63]. The healed burn injury, especially if healed by secondary intention, has compromised immune, lymphatic, and barrier function and is more at risk for continued injury. Like other forms of chronic scarring, most have latency periods of many years [68, 69].

Individuals with a family history of SCC may have an increased risk for developing the condition [70–72]. This may be due to genetic traits and inherited disorders similar to risk factors like sunlight [73, 74]. In general, SCC is thought to be more common in lower socioeconomic strata, primarily through occupational exposure to sunlight [75]. Multiple other toxins have been linked to SCC, including chronic exposure to arsenic, aromatic hydrocarbons, coal tar, petroleum-based oil, soot, and tobacco smoke [76–79].

Like many malignancies, SCC is not a solitary pathology defined by a single event that leads a cell toward carcinogenesis. Rather, SCC is the result of a collection of disparate acquired and genetic conditions which spawn the malignant transformation of suprabasal epidermal keratinocytes into a disease that ranges from easily managed, superficial tumors to metastatic, highly invasive lethal disease. This section reviews the etiology and pathogenesis of SCC, which shares many similarities with other non-melanoma skin cancers (NMSC).

The genetic origins of SCC lie in three principal categories, regardless of primary etiology of the genetic alteration: oncogenes, tumor–suppressor genes, and DNA-repair genes. Oncogenes are a group of growth-promoting genes derived from normal genomic sequences (so-called proto-oncogenes) involved in the regulatory control of cell growth and proliferation [80]. These are normally tightly controlled; however if mutated, proto-oncogenes can become oncogenes, leading to unchecked growth and malignant transformation. Mutations in the epidermal growth factor receptor (EGFR) proto-oncogene have been associated with SCC and are often linked to viral infection [81]. Human papillomavirus (HPV) is the most well-known cancer-inducing virus, linked to approximately 99.7 % of cervical SCC [82]. Despite this stalwart relationship, HPV’s role in SCC arising from venous stasis ulcers is less clear. Baldursson et al. demonstrated that while ~30 % of patients harbored HPV in their venous stasis ulcer, none of the ulcers that ultimately developed SCC contained the virus [83], suggesting either HPV is not involved in ulcer-derived SCC pathogenesis or the ulcer is subject to “hit and run” HPV infections [84].

Tumor-suppressor genes comprise a class of regulatory sequences that inhibit cell division, downregulate growth, or induce apoptosis. When mutated, cell growth and division can go unchecked, leading to malignant transformation and tumor development. The tumor-suppressor gene TP53, which encodes the commonly known tumor protein p53, plays a central role in SCC pathogenesis and is mutated in over 90 % of patients [85]. While UV irradiation and subsequent CC→TT substitution is the most common cause of p53 mutations, studies suggest that the chronic inflammation and proliferative derangement in lower extremity ulcers may also play a role. In one report, 50 % of patients with chronic venous stasis ulcers who ultimately developed SCC demonstrated overexpression of nonfunctional mutated p53, a rate similar to that found in chronic scars [86, 87].

Finally, DNA-repair genes maintain the integrity of the genome by correcting missense or nonsense mutations that occur normally during the cell division process. Some inherited disorders such as xeroderma pigmentosum arise from mutations in DNA-repair genes, ultimately leading to widespread SCC, BCC, and melanoma. However, there is no direct link between DNA-repair gene mutations and ulcers of the lower extremity; therefore this text will defer discussion of this topic.

The earliest association of chemical exposure and SCC was by Pott in 1775 in his report on the unusually high incidence of scrotal SCC among London’s young chimney sweeps [1]. While first attributed simply to “soot,” later studies confirmed that a chemical agent in soot, called benzo[a]pyrene, was responsible for the cancers [88]. Since then, dozens of chemicals have been associated with the development of SCC, many of which can cause ulceration of the extremities with topical exposure. Table 22.2 features carcinogenic agents linked to the development of SCC.

UVR remains the primary etiologic agent for SCC (and all skin cancer) carcinogenesis. Both UVA and UVB play a role in the development of SCC, specifically through damage of genomic DNA [89, 90]. It is estimated that patients with greater than 30,000 h of cumulative lifetime sun exposure are at higher risk for SCC development [42]. Given the protective nature of normal skin anatomy and its associated chromophores (most notably, melanin), it is reasonable to conclude that disruption of the normal protective layers of the skin through chronic wounds or ulceration would lead to higher susceptibility to UVR damage, though this specific question has not been studied. It is, however, important to understand the effect of UVR exposure on the development of chronic wounds, as the microvascular ablation and chronic inflammation in sun-damaged skin are significantly more prone to ulcerogenesis, regardless of the etiology [91].

While the concept of pre-SCC lesions has been intensely debated [92–94], it is now accepted that certain benign lesions are anatomic and genetic precursors to SCC [95, 96]. Chief among these is actinic keratosis (AK), which is thought to represent an early stage on the biologic continuum of SCC. After acne vulgaris, AK is the second leading cause for people to visit a dermatologist [38]. AK tends to appear on sun-exposed areas as the result of UVR exposure and appear as erythematous, rough, and scaly papules. Concerning physical findings that may indicate transition of AK to SCC include induration, pain, and ulceration. If a lower extremity cutaneous ulcer is biopsied and histopathology reveals AK, it is prudent to obtain additional sections of the biopsy sample as missed malignancies are common. Data from Carag et al. suggest that 33 % of tissue blocks initially revealing AK will yield further diagnoses if sectioned deeper, 3 % of which will demonstrate SCC [97].

In situ SCC, also called Bowen’s disease (BD), was one of the earliest described in situ precursors to invasive malignancy [98]. It can appear anywhere on the body, including both sun-exposed and non-sun-exposed areas, notably on women’s lower legs. Lesions may range from sub-centimeter to several centimeters in size and often present as oozing erythematous patches or plaques on the lower extremities. Histopathology typically demonstrates full-thickness atypia, which can reach from the stratum corneum to the basal cell layer, while preserving an intact basement membrane which distinguishes it from invasive SCC (Fig. 22.1). The likelihood that an untreated lesion will progress to SCC has been estimated at 3–5 % [99]. More importantly, the presence of BD indicates a patient’s increased susceptibility in developing other NMSC. Kao reported that in patients with BD, the incidence of either previous or subsequent NMSC was between 30 and 50 % [100], indicating the need for heightened screening in these patients, particularly if lower extremity ulceration is present.

The primary role of the clinician is to evaluate whether a lesion is suspicious for SCC, as early detection decreases morbidity, mortality, and associated costs. This should be followed by evaluation for tumors that are at highest risk for aggressive behavior. Therefore a detailed history and thorough physical examination is directed at identifying the variety of clinical manifestations. Skin biopsies are required to confirm the diagnosis and are useful for staging.