What is the origin of basal cell carcinoma (BCC)?

From the Guidelines

Basal cell carcinoma originates from the basal cells located in the lowest layer of the epidermis, which is the outermost layer of the skin, and is primarily caused by cumulative UV exposure, especially in fair-skinned individuals, as well as genetic factors such as nevoid basal cell carcinoma syndrome (Gorlin syndrome) 1. The development of basal cell carcinoma is a complex process that involves DNA damage from ultraviolet (UV) radiation exposure, which triggers mutations in the basal cells, causing them to multiply uncontrollably instead of following their normal growth cycle.

• The most significant risk factor is cumulative UV exposure, especially in fair-skinned individuals, with fair skin, red or blond hair, and light eye color being associated with BCC as independent risk factors due to greater susceptibility to UV damage 1.
• Genetic factors also play a role, with certain inherited conditions like nevoid basal cell carcinoma syndrome (Gorlin syndrome) predisposing individuals to develop multiple basal cell carcinomas, and other contributing factors include chronic sun exposure, advanced age, immunosuppression, exposure to arsenic, and previous radiation therapy 1. Some key points to consider in the development and management of basal cell carcinoma include:
• The cancer typically develops on sun-exposed areas like the face, ears, and neck, appearing as pearly or waxy bumps, flat flesh-colored lesions, or bleeding or scabbing sores that don't heal properly.
• While basal cell carcinomas rarely metastasize, early detection and treatment are important to prevent local tissue destruction and cosmetic disfigurement, and patients should be counseled on sun protection and avoidance of ionizing irradiation unless absolutely necessary 1.

From the Research

Origin of Basal Cell Carcinoma

The origin of basal cell carcinoma (BCC) is a complex process involving multiple factors.

• BCC is the most common malignant skin cancer, with a high incidence in white individuals, especially those with fair skin 2.
• The most important risk factor in the development of BCC is UV radiation, with short-wavelength UVB radiation playing a greater role than long-wavelength UVA radiation 2.
• The latency period between UV damage and the clinical onset of BCC is typically 20-50 years, resulting in BCC developing on chronically sun-exposed skin in elderly people, most commonly in the area of the head and neck 2.

Genetic Mutations and Signaling Pathways

• Genetic mutations, especially in the hedgehog pathway, play a crucial role in BCC pathogenesis 3, 4.
• The patched/hedgehog intracellular signaling pathway is central to both sporadic BCCs and nevoid BCC syndrome (Gorlin syndrome) 4.
• Mutations in the TP53 tumor-suppressor gene and the PTCH gene are common in BCC, with UV-induced mutations in TP53 present in about 50% of BCC cases 2, 5.
• The sonic hedgehog protein and the smoothened (SMO) protein are also involved in BCC formation, with SMO inhibitors being used to treat advanced forms of BCC 4.

Alternative Mechanisms of Mutagenesis

• BCCs arising at sun-protected sites, such as the genital skin and perianal area, may have alternative mechanisms of mutagenesis, as they do not harbor a UV mutation signature 6.
• These BCCs still display recurrent PTCH1 alterations, supporting their classification as bona fide BCCs 6.
• The presence of upstream Hh pathway alterations in sun-protected BCCs suggests their susceptibility to Hh pathway inhibitors 6.

Risk Factors and Epidemiology

• Other risk factors for the development of BCC include sun bed use, family history of skin cancers, skin type 1 and 2, immunosuppression, previous radiotherapy, and chronic exposure to toxic substances such as inorganic arsenic 2, 3.
• Epidemiologic studies demonstrate a higher incidence of BCC in more equatorial latitudes than in polar latitudes 2.
• The incidence of BCC is increasing worldwide, with a significant impact on public health 3.