17.1Introduction

Cutaneous squamous cell carcinoma is the second most common malignancy in white persons [1]. Various studies have estimated its annual incidence to be between 87,000 and 760,000 with an increasing incidence over time and much higher incidences in the south and southwest USA [2–9]. A white male born in the USA in 1994 has an estimated lifetime risk of 9–14% of developing a cutaneous SCC, while a white woman’s estimated risk is 4–9% [8]. Despite very high cure rates for most SCC, approximately 4% metastasize to lymph nodes and 1.5% result in death [10]. It can be estimated from these figures that SCC accounts for 1,300–11,000 deaths annually in the USA. As a point of reference, melanoma kills 8,600 persons annually. Nearly all deaths occur in those who have tumors with known risk factors [11]. Therefore, understanding classic and highly curable SCC and differentiating it from high-risk disease are crucial in appropriately managing SCC. However, as will be discussed, the subset of SCC which carries a high risk of metastasis and death has not been well defined, and the risks have not been well quantified. Subsequently, there is currently little consensus regarding optimal staging and treatment for high-risk patients making it difficult for clinicians to advise these patients with confidence [12].

Summary: Pathophysiology (Risk Factors for SCC Development)

•In order to prevent squamous cell carcinoma and effectively manage it once it occurs, physicians should be familiar with mechanisms of disease development, including risk factors associated with tumor formation. Genetic factors as well as external influences contribute to tumor development.

17.2Pathophysiology (Risk Factors for SCC Development)

Cutaneous squamous cell carcinoma is a neoplasm arising from epidermal keratinocytes. Identification of the host and environmental factors associated with the development of cutaneous SCC has provided insights into the

mechanisms leading to tumor development. Intrinsic host risk factors include age, skin phototype, the presence of immunodeficiency disorders, and genodermatoses resulting in defective DNA repair (xeroderma pigmentosa), defective melanin production (oculocutaneous albinism), or chronic cutaneous inflammation (epidermolysis bullosa) [13–15]. Immunosuppressive conditions such as leukemia and lymphoma result in an increased risk of SCC as well. Extrinsic or environmental factors are many and include, most commonly, exposure to medical ultraviolet (UV) light treatments or natural UV radiation. The latter accounts for higher skin cancer rates in geographic latitudes nearer the equator and in people with outdoor occupations [1, 15]. Other iatrogenic factors include exposure to ionizing radiation, organ transplantation, immunosuppressive medications, and treatment with psoralens prior to UVA radiation. Infectious contributors include high-risk strains of the human papilloma virus (in anogenital SCC), HIV/AIDS, and chronic infections such as osteomyelitis. Chronically injured skin is at increased risk, as with chronic radiation dermatitis, sinus tracts, ulcers, and burn scars. In particular, patients with dystrophic epidermolysis bullosa have a very high risk of mortality from SCC. Chemical carcinogens include arsenic and polycyclic aromatic hydrocarbons [4, 13, 14, 16–23].

17.2.1 Ultraviolet Light

The most common cause of cutaneous SCC is exposure to ultraviolet radiation, with UVB (290–320 nm) accounting for most of the carcinogenic effect. UVA (320–400 nm) plays a lesser, but additive, role. Cutaneous SCC may arise de novo, or from a precursor lesion. Most commonly, UV radiation generates pyrimidine dimers within the sequence of the p53 tumor suppressor gene. When both copies of p53 within the keratinocyte are mutated or dysfunctional, the cell undergoes clonal expansion. This results in the formation of actinic keratoses, squamous cell carcinoma in situ, and, with persistent proliferation, invasive SCC. P53 is mutated in 90% of SCC [24]. While it is difficult to determine the likelihood of an individual AK progressing into an invasive SCC, this has been estimated at 0.1–10% [25–27]. The presence of multiple AKs serves as a marker of increased risk of developing SCC. Patients with greater than 10 AKs have a 14% probability of developing an SCC within 5 years [28]. Their presence

further serves as a marker of high cumulative lifetime sun exposure and therefore an increased risk of other UV-related malignancies such as basal cell carcinoma.

17.2.2 Human Papilloma Virus

Both bowenoid papulosis and the autosomally inherited disorder epidermodysplasia verruciformis (EDV) are premalignant disorders that may progress to invasive SCC. Both disorders are associated with human papilloma viruses (HPVs), small, double stranded DNA viruses which have a specific tropism for stratified squamous epithelium. While bowenoid papulosis is most commonly associated with high-risk HPV types 16 and 18 (genus alpha-papilloma virus), EDV subtypes (genus beta-papilloma virus) include 23 variants. In patients without EDV, beta species 1 HPV types (HPV 5, 8, 12, 14, 19, 20, 21, 24, 25, 36, 47, and 93) have been shown to be more commonly associated with benign warts, while beta species 2 HPV types (HPV 9, 15, 17, 22, 23, 37, 38, and 80) have been shown to be associated with SCC [29]. Conversely, in patients with the inherited disorder of EDV, HPV 5 and 8 appear most commonly and have been identified in up to 90% of SCCs in these patients [30, 31]. In solid-organ-transplant recipients, an increased prevalence of the beta-HPV subtypes is seen, with 90% of SCCs in renal transplant patients containing HPV-beta DNA. However, a pathogenic role of HPV has not been established in transplantassociated SCC.

While the role of HPV in cutaneous SCC in transplant patients remains debated, the presence of HPV (most commonly 16) in 70–90% of anogenital SCC [32–34] has lead to an accepted causal association. While the incidence of anal cancer is increasing at a rate of 2% per year [35], HIV infected men and women are at substantially increased risk of developing all types of anogenital HPV-associated in situ and invasive malignancies. For patients under 30 who are HIV positive, the relative risk of vulvovaginal and penile cancer is 37, and for anal cancer >100 [36].

The oncogenic mechanism of action of high-risk HPV types is via the ability of the E6 protein, primarily of types 16 and 18, to promote the ubiquitin-depen- dent degradation of the tumor suppressor, p53. Similarly, the oncoprotein E7 interacts with the tumor suppressor pRb, inducing the degradation of the Rb

protein, and activating telomerase, which leads to cell cycle progression [37, 38]. While all subspecies of HPV possess the E6 and E7 proteins, their malignant potential in the HPV-beta subspecies is thought to be weaker than in the high-risk types. The importance of intact cytotoxic T-lymphocyte activity against HPV E6 and E7 proteins is hypothesized to play a critical role in clearance of the virus and is impaired in those infected with HIV. This may partially explain why HPV infection is so strongly linked to anogenital SCC in this patient group [39].

17.2.3Molecular and Genetic Factors Impacting SCC Development

While knowledge regarding the importance of p53 and HPV in the development of SCC has grown over many years, recent discoveries regarding the role of the immune system in SCC and the genetic and molecular mechanisms underlying keratinocyte proliferation and migration allow for better potential understanding of invasive tumor development, particularly in immunosuppressed patients. The point at which keratinocytes develop the capacity for invasion has been linked to the loss of expression or function of p16 [40], a protein that is not expressed during the normal wound healing process. Concomitantly, lami- nin-332 has been shown to be co-expressed with p16 at the transition point from in situ to invasive disease. Further study has revealed that a precursor form of laminin-332 may be responsible for the induction of the coordinated production of functional laminin-332 and p16 leading to hypermobility and growth arrest during wound healing and early invasion of neoplastic keratinocytes [41]. Additional studies have shown that there is increased lymphatic vessel density within SCC as well as increased expression of VEGF-C, important in lymphangiogenesis, in the peritumoral microenvironment [42]. Differential gene expression studies in SCC as compared with non-malignant hyperproliferative disease have implicated multiple tumor suppressor genes, the WNT signaling pathway, and variable expression of matrix metalloproteinases in the pathogenesis of SCC [43]. Additionally, the areas surrounding SCC tumors contain an abundance of T-lymphocytes which fail to control tumor growth. Interestingly, approximately 50% of T-cells surrounding SCCs have been shown to be FOXP3+ T regulatory