EPIDEMIOLOGY AND ETIOLOGY OF NON MELANOMA

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) constitute the majority of nonmelanoma skin cancers (NMSCs):
- Which are also referred to as “keratinocyte cancer”
Keratinocyte cancer:
- Represents about 95% of malignant skin tumors estimated at greater than 5.8 million cases annually
While BCC (3.6 million cases annually) is four to five times more common than SCC (1.8 million cases annually):
- The incidence of both tumor types continues to rise despite growing awareness of the risk factors for these skin cancers
The overall incidence increases with age:
- Is known to be higher in men than in women
Development of NMSC is multifactorial and is related to various genotypic, phenotypic, and environmental risk factors:
- Ultraviolet (UV) solar radiation:
  - Is considered to be the dominant risk factor for the development of both BCC and SCC:
    - Supported by the fact that most of these tumors tend to present on sun-exposed areas of the body
  - The development of BCC is thought to arise from intense intermittent sun exposure:
    - Leading to burns
  - Whereas SCC appears to be linked to the cumulative dose of UV solar radiation over time
  - Sun exposure earlier in life appears to be more influential in skin cancer development than that received later in life
  - Markers of UV sensitivity (e.g., fair skin, light eyes, blond or red hair) and intensity of exposure (i.e., increased incidence for individuals living in proximity to the equator):
    - Are associated with increased NMSC risk as is additional UV exposure from recreational tanning booths and UV light therapy:
      - One case-controlled study demonstrated that the use of tanning devices was associated with an estimated twofold risk for both SCC (odds ratio = 2.5) and BCC (odds ratio = 1.5)
      - Karagas et al. reported that treatment of psoriasis with oral psoralen in combination with light treatment (PUVA therapy) resulted in an increased adjusted relative risk of 8.6 for SCC while the risk for BCC was much lower
      - UV-induced mutations in the p53 tumor suppressor gene is thought to be a common event in NMSC development
- Another important risk factor for both BCC and SCC:
  - Is immunosuppression:
    - Long-term immunosuppression therapy such as that used for solid organ transplant has been shown to increase the risk of SCC over 100-fold and for BCC about 10-fold
    - SCC in immunosuppressed patients tend to be behave more aggressively and are associated with greater tumor depth, higher risk of recurrence, and more frequently associated with perineural or lymphovascular invasion:
      - However, BCCs have not been found to be more aggressive in solid organ transplant recipients than the general population
  - Patients with acquired immunodeficiency syndrome also have an increased incidence of NMSC, and factors such as persistent human papilloma virus (HPV) infection may act synergistically with UV exposure to increase risk:
    - Moreover, HPV infection, especially HPV 16 and 18, has been implicated in the development of anogenital SCC
- Exposure to ionizing radiation:
  - Increases the risk of NMSC threefold and often presents decades after initial exposure
    - This risk has been shown to be dose dependent
- Chemical exposures:
  - Such as arsenic, tar, soot, tobacco, asphalt, and mineral oil:
    - Have all been associated with an increased risk of SCC
- SCC can also arise from areas of chronic inflammation and healing such as from:
  - Scars, burn sites, or ulcers:
    - This type of SCC is also known as a Marjolin ulcer
- Patients with genetic syndromes including:
  - Xeroderma pigmentosum, albinism, Muir–Torre syndrome, dystrophic epidermolysis bullosa, Fanconi anemia, Werner syndrome, nevoid basal cell syndrome, and Li–Fraumeni syndrome have an increased incidence of NMSC:
    - Xeroderma pigmentosum:
      - Is a rare autosomal recessive disease characterized by:
        
        Photophobia, severe sun sensitivity, and advanced sun damage:
        
        Affected individuals have defective DNA excision repair, and when exposed to UV radiation, develop malignancies of the skin and eyes at a rate 1,000 times that of the general population
      - Aggressive sun protection in the form of full-body sun suits and regular skin examinations are critical for patients with xeroderma pigmentosum
      - Ideally, these patients should only go outside at night
  - Nevoid basal cell syndrome:
    - Is an autosomal dominant disorder characterized by the development of multiple BCCs:
      - BCCs in patients with nevoid basal cell syndrome are often quite small but can number in the hundreds on any given skin surface
    - The sonic hedgehog signaling pathway (PTCH1 gene, chromosome 9q):
      - Has been recognized as having a significant etiologic role in nevoid BCC syndrome, and is also present in 90% of sporadic BCC
    - These patients are exquisitely sensitive to radiation and should avoid excessive sun exposure and radiation therapy
  - Regular follow-up is important, as such tumors are difficult to monitor and treat
Similar to other tumor types, a previous diagnosis of cutaneous carcinoma:
- Increases the risk of future NMSCs to as high as 35% at 3 years and 50% at 5 years