BASAL CELL CARCINOMA (BCC)
This epithelial Tumours arises from the basal layers of the epidermis and its appendages (Fig. 1).
Fig. 1 The typical appearance of a BCC
It is locally invasive, metastasis being excessively rare. It is the most common skin Tumours affecting light-skinned people and appears predominantly in sun-exposed areas of the skin (head and neck predominantly although also on the trunk). It is indeed the commonest cancer overall. Arsenic is a known predisposing environmental agent (Boonchai et al. 2000) but is now a rare cause. BCC may occur after radiotherapy: it was seen in the past as multiple lesions on the scalp as a sequel of the use of radiotherapy to treat scalp ringworm and now is seen more commonly as a late result of radiotherapy to treat cancer or even noncancerous conditions such as ankylosing spondylitis. The clue to the cause is the distribution so that multiple lesions in a rectangular distribution along the spine, for example, are more likely to be related to radiotherapy than genetic susceptibility. In a recent registry-based study from the Netherlands of 444,131, histologically confirmed cases between 1973 and 2008, age- adjusted incidence rates (European Standard Population) increased approximately threefold from 40 to 148 per 100,000 in males and from 34 to 141 in females. Lifetime risk of BCC was 1 in 5–6 for Dutch citizens (Flohil et al. 2011).
Most cases of BCC are sporadic but there is some evidence for clustering in families (de Zwaan and Haass 2010), and association studies have shown a similar relationship to pigment genes as for melanoma. Red-haired individuals are particularly sun sensitive, and therefore it is not surprising that variants in genes associated with red hair are associated with increased risk such as the melanocortin 1 receptor gene (MC1R) (Scherer et al. 2008; Han et al. 2006; Bastiaens et al. 2001a, b; Box et al. 2001a, b) and the agouti signaling protein locus (ASIP) (Nan et al. 2009). Polymorphisms in other pigment genes are also associated with risk such as the oculocutaneous albinism A2 gene OCA2 (Box et al. 2001a, b) SLC45A2 (Stacey et al. 2009a,b) and the interferon regulator gene 4, IRF4 (Han et al. 2011). Loci not known as yet to be associated with pigmentation but which have been shown to be associated with susceptibility in GWAS include a gene coding for keratin 5, a locus near to the CDKN2A locus at 9p and TERT which codes for telomerase and therefore impacts on telomere length (Stacey et al. 2009a, b; Baird 2010). BCC and melanoma are therefore both associated with pigment genes, and it is not therefore surprising that patients not infrequently get both (Farndon et al. 1992; Gorlin 1984; Guarneri et al. 2000; Happle 2000).
Genetic disorders associated with a predisposition to basal cell carcinoma include Gorlin syndrome (the nevoid basal cell carcinoma syndrome) in which a characteristic facies, bony anomalies, odontogenic dental cysts, and palmar pits precede the development of multiple BCC. The number of BCC is increased in those with greater sun exposure, and radiotherapy significantly increases Tumours risk both in the skin and the meninges and therefore must be avoided if at all possible. Rarer Tumours include medulloblastoma and ovarian fibromas. In the UK, around 1 in 30,827 people is affected (prevalence) (Evans et al. 2010). Inherited mutations in the “patched” PTCH1 gene at 9p 22.3 have been shown to be the cause of the nevoid basal cell carcinoma syndrome (Hahn et al. 1996; Johnson et al. 1996), loss of the second allele of PTCH1 occurring somatically to cause BCC in gene carriers over time. Patched is a negative regulator of the hedgehog pathway which is a pro-proliferative signaling pathway which is now known to be important in a number of cancers as well as BCC (de Zwaan and Haass 2010). Sporadic basal cell carcinomas show chromosome 9q allele loss, and mutations in the “patched” gene which causes the basal cell nevus syndrome have been detected with high frequency in such Tumours.
This supports the view that the “patched” gene is a gatekeeper for common skin cancers. Patched controls the activity of “smoothened,” and recent therapeutic developments for BCC have included the exploration of smoothened inhibitors (Skvara et al. 2011) for the treatment of very advanced disease.
Increased susceptibility to BCC is also seen in xeroderma pigmentosum, porokeratosis, albinism, Bazex–Dupré–Christol syndrome, and the rare Rombo syndrome (Van Steensel et al. 2001).