The prevalence of cSCC is increasing globally, with lifetime incidences estimated to be 9–14% in males and 4–9% in females [1]. CSCC is a type of non-melanoma skin cancer (NMSC) [2]. Other NMSCs include cutaneous lymphoma, Merkel cell carcinoma, and Kaposi’s sarcoma, which account for less than 1% of all NMSCs ^[2][3][2,3]. The most common cause of cSCC is UV radiation exposure, as it induces mutations in the keratinocyte p53 tumor-suppressor gene ^[1][4][1,4]. Less common causes of cSCC include long-term exposure to cigarette tar, high-degree burn scars, non-healing ulcers or sores for several years, and certain variants of human papillomavirus (HPV) [5]. In recent years, research on chronic immunosuppression and inflammation has elucidated the pathways contributing to tumorigenesis in cSCC ^[1][6][1,6].

Of all NMSCs, cSCC accounts for the majority of morbidity from metastatic burden. Therefore, early identification and management of cSCC is vital to prevent neoplastic advancement [6]. Though histopathology and surgery are the status quo and gold standard for analysis and management of cSCC, newer in vivo optical imaging diagnostic devices can increase the “real time” analytic accuracy of detecting cSCC and other cutaneous pathologies [6]. These devices include reflectance confocal microscopy (RCM), optical coherence tomography (OCT), and line-field confocal optical coherence tomography (LC-OCT) [6]. These devices allow for faster identification and selection of clinically relevant cases for prudent biopsy; they also provide a convenient and precise method of monitoring cSCCs over time [6]. Additionally, newer pharmacological interventions provide convenient ways to treat multiple in situ/low-risk cSCCs (e.g., epidermal growth factor receptor inhibitors and immune checkpoint inhibitors) in cases of locally advanced and metastatic cSCCs [6].

2. Epidemiology

SCC is the second-most predominant skin malignancy in the USA after BCC [1]. The incidence of cSCC is more than one million per year in the US [7]. Data from the Mayo Clinic’s Rochester Epidemiology Project showed a 263% increase in cSCC incidence between 1976 to 1984 and 2000 to 2010 [8]. Historically, the incidence ratio of SCC to BCC was 3:1 but recent studies suggest that the ratio approaches 1:1 in patients of advanced age [9]. Thus with increasing elderly populace and skin cancer screening, the incidence rates of cSCC are rising progressively [9]. CSCC typically arises in men with light skin (Fitzpatrick-III or lower) with a history of chronic, unprotected UV radiation exposure [6]. On average, cSCC arises in the 5th decade of life typically in areas of sun-exposed skin [6]. CSCC is also prevalent in patients with chronic immunosuppression who are at risk of conversion into more aggressive subtypes ^[6][10][6,10].

3. Pathogenesis

The pathogenesis of cSCC is multifactorial and dependent upon environmental and genetic factors [11]. CSCCs have the presence of keratin pearls, which signify squamous differentiation, and can be classified into histologic subcategories [11]. UV radiation induces mutations in the keratinocyte p53 tumor-suppressor gene commonly seen in progressive keratinocyte dysplasia which begins with actinic keratosis evolving into SCC in situ (SCCIS) and finally invasive SCC [12]. The use of UV radiation from tanning lamps, phototherapy and ionizing radiation are associated with increased rates of cSCC, via dysregulation of the p53 pathway ^[12][13][12,13]. Other major gene mutations associated with tumorigenesis in cSCC include tumor protein 53 (TP53), CDKN2A, Ras, and NOTCH1 ^{[14][15][16][17][18]}[14,15,16,17,18]. The majority of TP53 mutations consist of a single-base transition mutation at dipyrimidine sites in cSCC [17]. The loss of TP53 leads to the loss of apoptosis allowing cancerous cells to grow clonally [18]. Loss of function of the cyclin-dependent kinase inhibitor 2A (CDKN2A), which regulates the cell cycle checkpoint proteins [19], continuous activation of RAS-signal-transducing proteins; or Notch homolog 1 tumor-suppressor gene support cSCC development [20]. In addition, cSCC is a heterogenous disease that may have many undiscovered driver mutations [21]. Premalignant keratinocyte lesions such as actinic keratoses have been reported to have mutations in TP53 and RAS as well [21], but further mutations may be necessary for tumor progression and development [21]. This molecular basis of pathology can aid in the development of targeted therapies, though the myriad mutations in cSCC poses a challenge against the effectiveness of single-agent targeted therapy [22].

4. Etiology

Risk factors for cSCC are male gender, Fitzpatrick skin types I-III, age over 50, UV radiation exposure, immunosuppression, human papillomavirus (HPV) [23] infection, chronic wounds, environmental exposures, and familial cancer syndromes [14]. Environmental agents causing cSCC include arsenic-contaminated well water ^[24][25][24,25], insecticides with lead arsenate, aromatic polycyclic hydrocarbons (e.g., tar, terrain, and ash), nitrosamines, and alkylating agents ^[26][27][26,27]. Exposure to ionizing radiation, even in limited quantities, has also been linked with more aggressive forms of cSCC (10–30%) ^[28][29][28,29]. Organ transplant recipients (OTRs) have a 20 to 200 times higher risk of cSCC compared to the general population due to lifelong immunosuppression [30]. CSCC formation is proportional to the number of lifetime-use immunosuppressive agents in an OTR ^[31][32][31,32]. Heart and lung transplant recipients are at higher risk of cSCC than renal transplant recipients due to older average age at time of transplant and aggressive immunosuppressive treatment (e.g., azathioprine and cyclosporine) ^[31][33][31,33]. The risk of cSCC development in solid OTRs is also higher than recipients of hematopoietic stem cell transplant [34]. In a cohort of kidney transplant recipients in the U.K., 30% developed cSCC within a decade of the transplant [35]. Patients with chronic lymphocytic leukemia have an 8- to 10-fold higher risk of concomitant cSCC development due to deficiencies in both cell-mediated and humoral immunity [36]. Improving T-cell-mediated antitumor activity can be supportive in regulating advanced cSCC due to the prominent role of antitumor immunological surveillance [37]. Currently, cemiplimab is a programmed death protein 1 (PD1) inhibitor under study, approved in 2018 for locally invasive or metastatic cSCC in patients who are not surgical candidates [37]. Oncogenic subtypes of HPV are preferentially linked to periungual and anogenital cSCC [26]. HPV 16 and 18 subtypes produce E6 and E7 oncoproteins which enable cancerous cells to avert apoptosis and permit the perpetual replication of viral DNA by interfering with the activity of tumor-suppressor genes p53 and retinoblastoma protein (rbp), respectively ^[26][38][26,38]. CSCCs in OTRs may also express HPV subtypes 8, 9, and 15 [39]. HPV is transcriptionally inactive in cSCC as confirmed by examining viral messenger RNA level [40]. This indicates that HPV is potentially engaged in the induction phase of pathogenesis of cSCC but not in the maintenance phase [40]. Defects in the production of antioxidant melanin or increased genetic instability can increase the risk of developing cSCC [41]. For example, albinism, the congenital absence of melanin, is highly associated with a high risk of cSCC development [42]. Uncommon familial cancer syndromes linked with defective DNA repair or photosensitivity can predispose younger individuals to develop multiple cSCC [41]. Xeroderma pigmentosum (XP) is another genetic condition that can predispose young individuals to develop skin cancer [43]. XP is an autosomal recessive pathology that decreases skin’s ability to repair DNA damage thus the median age of NMSC development is 18 years [43]. XP arises due to a defect in post-replication repair or DNA nucleotide excision ^[43][44][43,44]. Patients with XP can develop diffuse erythema, bullae, blisters, and ensuing xerosis and scaling with minimal sun exposure ^[43][44][43,44]. In patients with XP, there is 16-fold greater risk for developing cSCC ^[43][44][43,44]. Figure 12 summarizes etiological causes of cSCC.

5. Clinical Presentation

CSCC commonly develops on the face, bald scalp, neck, dorsal hands, and extensor forearms from a precursor lesion, actinic keratosis ^[45][46][45,46]. Body areas with the highest incidence of metastasis include the head and neck, and especially the ear and nonglabrous lip ^[47][48][47,48]. Classically, cSCC appears as erythematous plaques or papules with variable levels of hyperkeratosis, scaling, crusting, and ulceration, with or without telangiectasia or bleeding [12]. CSCC may also appear smooth, nodular or plaque-like with induration and/or subcutaneous spread ^[12][13][12,13]. Seldomly, cSCC can elicit pain and tenderness, signifying perineural invasion ^[12][13][12,13]. Perineural invasion is linked with local neuropathic symptoms, e.g., burning, numbness, paresthesia, or paralysis [49]. Involvement of the non-sun-exposed areas is common in medium brown to dark brown toned skin, though in ivory- to light-brown-toned skin cSCC typically develops on the sun-exposed areas ^[50][51][50,51].