Non Melanoma Skin Cancers

• 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 3.5 million cases annually
• While BCC is four to five times more common than SCC:
  • 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 and 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 the development of 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
      • 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
      • Advanced sun damage
    • Affected individuals have defective DNA excision repair:
      • 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:
      • 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
• DIFFERENTIAL DIAGNOSIS
  • Several epidermal tumors common to the skin can resemble or are precursors to NMSC:
    • Recognition of these tumors is important for both tumor surveillance and cancer prevention
  • Seborrheic keratoses:
    • Are benign proliferations of epidermis that can appear on any part of the skin:
      • Except mucous membranes:
        • Usually appear after the age of 30 years
    • They are not related to sun exposure:
      • But are common on the face, neck, and trunk:
        • Often in large numbers
    • They initially appear as:
      • Flat brown macules:
        • Eventually becoming larger, “stuck-on” brown plaques with dull crumbly surfaces
    • Seborrheic keratoses can sometimes be confused with melanoma:
      • Biopsy of these lesions is prudent if any sudden changes in size or color occur

• Actinic keratoses (AKs):
  • • Are premalignant lesions:
      • With the potential to develop into SCCs
    • They are found mainly on sun-exposed areas
    • These lesions most commonly present as:
      • Skin-colored, erythematous, or brown ill-defined patches with adherent scales
    • These lesions are extremely common on the:
      • Face, scalp, ears, and lips and can often be better appreciated by palpation rather than by inspection with the naked eye

• Keratoacanthoma:
  • Is a tumor that often occurs on older, sun-damaged skin:
    • Is most commonly found on the:
      • Neck and face
    • These tumors originate in:
      • The pilosebaceous glands:
        • May grow rapidly as a red- or skin-colored dome-shaped nodule with a central crater:
          • Maximum size may be attained at 6 to 8 weeks with slow regression over a period of months leaving a residual scar
  • These tumors can be confused both clinically and histologically with SCC:
    • There are reports of progression of keratoacanthomas to invasive or metastatic carcinoma
  • Classification of these tumors as a:
    • Well-differentiated variant of invasive SCC has been proposed
  • Surgical excision of keratoacanthomas with 3- to 5-mm margins is recommended, and Mohs surgery may be employed in cosmetically sensitive areas
  • These tumors are radiation sensitive if surgery is not an option
• A cutaneous horn:
  • Is the clinical description for a growth that appears as a dense cone of epithelium resembling a horn
  • They range in size from several millimeters to over a centimeter and are generally white or yellowish in color
  • They also tend to appear on sun-exposed skin of older individuals
  • Histologically, cutaneous horns can develop from:
    • Benign lesions such as:
      • Warts
      • Seborrheic keratoses
    • Premalignant lesions such as:
      • AKs
      • SCCs in situ
    • Malignant lesions such as:
      • SCCs
  • Up to 15% of cutaneous horns demonstrate invasive SCCs at the base:
    • Excision of these tumors is always indicated
• Nevus sebaceous:
  • Is a benign tumor of the scalp:
    • That appears at or soon after birth as a yellowish-orange, well-demarcated plaque
  • Initially, the surface has a:
    • Smooth or waxy appearance that gradually becomes more warty or verrucous during puberty
  • In adulthood, approximately 10% of these lesions develop into BCC:
    • It is therefore recommended that these lesions be excised or closely monitored for the life of the patient.

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