# Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention
## 5 NAD+ Status and Skin Cancer
### Cutaneous Squamous-Cell Carcinoma  
Cutaneous squamous-cell carcinoma (cSCC) is one of the most common cancers in Caucasian populations, representing 20% of all cutaneous malignancies. It usually arises from the in situ lesion actinic keratosis (AK), or it may grow de novo in photo-exposed areas. The main known risk factors are advanced age, cumulative sun exposure, fair skin, prolonged immunosuppression, human papillomavirus infection, male gender, and previous diagnosis of cutaneous tumors [82; 83]. Outdoor workers and people with weakened immune systems by therapies or chronic infectious diseases have a higher risk of developing cSCCs [82].  
AK is a limited area of irregular epidermal growth, caused by excessive solar exposure, visible as a thickened, cornified, scaly lesion characterized by keratinocyte atypia. The degree of intraepidermal involvement by this atypia is graded as mild (AKI), moderate (AKII), or severe (AKIII). AKIII is considered as an in situ cSCC (iSCC) [84]. Indeed, AK and cSCC are stages of a continuous multistep process that derives from p53 gene mutation and proliferation of atypical keratinocytes. Cumulative sunlight exposure, impaired DNA repair, immune response dysregulation, and changes in the surrounding stroma favor this transition and the disease progression. Clinical studies have estimated that 65% of cSCCs emerge from the site of an AK lesion [85]. Moreover, up to 16% of AKs progress to invasive cSCCs, with extrapolation studies which estimate the risk of progression at 10%.  
This progression takes approximately two years [83]. Thus, if left untreated, AK may often progress to cSCC, thus causing increased morbidity [85]. The exact incidence rate of AK and cSCC is unknown because in most countries these lesions are not reported in cancer registries. The highest prevalence of AK is reported from Australia (up to 60%), an area with intense UV irradiation home to a large fair-skinned population. In Europe, a prevalence of 15% in men and 6% in women has been reported. In the same study, 34% of males and 18% of females aged 70 years or older had AKs [38]. In Europe, cSCC showed a marked geographic variation with the highest incidence rates in South Wales (31.7 per 100,000 person-years) and Switzerland (28.9 per 100,000 person-years) [38]. Invasive cSCC has the potential to recur (8%) and metastas (5%) [86]. AKs can occur as single lesion or arise from the field cancerization (FC), a chronically photo-injured skin area in which clinical and subclinical lesions coexist. The presence of multiple AKs is a marker of increased risk of developing invasive cSCC, and early treatment of AKs reduces the probability of progression [38; 83; 84].  
As the individual risk of progression from AK to invasive cSCC cannot be accurately predicted, it is preferable to treat the entire FC. Indeed, the clinical grading of AKs has scarce prognostic value, although it may be useful in guiding treatment choices [85]. Different approaches are available to treat AKs. Ablative procedures such as cryosurgery, curettage, laser ablation, and surgical excision are generally used to treat single lesions; many topical treatments (e.g., photodynamic therapy, 5-fluorouracil (FU), ingenol mebutate, diclofenac 3% gel, and imiquimod) may be employed to treat both individual lesions and the FC. At 12-month follow-up, the reported sustained clearance rate of initially cleared individual AKs is 28% for cryosurgery, 54% for 5-FU, 59% for PTD, 73% for imiquimod, 81% for diclofenac 3% gel, 87% on face and scalp or trunk and extremities for ingenol mebutate. However, these treatments are poorly effective on AKIII lesions and FC [84].  
Chemoprevention represents the use of pharmacological interventions to potentially interrupt the development of new malignancies. Indeed, chemopreventure agents might reduce the incidence of AKs in the FC by inhibiting the early effects of UV radiation. They are becoming a viable strategy to prevent or reduce AK relapse and cSCC occurrence [85].