Aetiology
Similar to pre-malignant skin tumours such as actinic keratoses, the incidence of non-melanoma skin tumours varies dramatically depending on skin phototype or constitutive pigmentation, cumulative sun exposure, and geographic latitude. In addition to solar ultraviolet (UV) exposure, other factors are known to increase the risk of squamous cell carcinoma (SCC), such as ionising radiation; burns; previous psoralen and UV-A light therapy; hereditary skin conditions; environmental toxins such as arsenic, soot, and tar; human papillomavirus; and some immunocompromised states.[21][22][23][24]
SCC arising only in the red inked areas within a multi-coloured tattoo has been described, suggesting that red tattoo ink in the skin may be an infrequent risk factor for developing SCC.[25]
Pathophysiology
SCC arises in keratinocytes that have undergone uncontrolled proliferation due to mutations and malignant transformation of the cells.[26] UV light is absorbed into the skin and can produce immediate erythema and sunburn, and over time, photo-ageing and skin cancers. Laboratory studies have shown that the UV-B region (290-320 nm) of the solar spectrum is primarily responsible for these effects.[27] Chronic UV exposure may cause mutations in cellular DNA. The accumulation of genetic abnormalities leads to malignant transformation, uncontrolled proliferation, and cancer formation.[28]
It is widely accepted that SCCs develop through a multi-step process that involves the activation of proto-oncogenes and/or inactivation of tumour suppressor genes.[29][30][31] The initial damage takes place in the DNA, after which DNA is repaired by a complex array of gene repair proteins.[32]
Research has produced some key insights into some of the underlying mechanisms of carcinogenesis.
Levels of PTEN (a tumour suppressor that functions as a negative regulator of AKT/p38 signalling) have been demonstrated to be reduced in SCC in mice. This also occurs in human actinic keratoses and SCCs, supporting a key role for PTEN in preventing human skin cancer formation and progression.[30]
Ciclosporin is associated with an increased risk of skin cancer, specifically SCC. It is thought to promote skin cancer through immunosuppression; however, studies suggest an immunosuppression-independent mechanism in skin carcinogenesis by promoting primary skin tumour growth in immune-deficient mice and keratinocyte growth in vitro as well as enhances keratinocyte survival from removal of extracellular matrix or UV-B radiation.[33] Ciclosporin may also impair the genomic integrity of keratinocytes in response to UV-B.[34]
Elevated vascular endothelial growth factor A (VEGF-A), which plays a key role in angiogenesis of human skin, is present in SCC. A micro RNA, miR-361, which regulates VEGF-A production, has been shown to be decreased in SCC compared with normal skin and might play a role in skin cancers.[35]
Other pathways have been implicated in the pathogenesis of cutaneous SCC, for example:[36][37][38][39]
Elevated expression of COX-2
Elevated expression of CXCR7
Upregulation of CD109
Point mutation of KNSTRN
Classification
Types of SCC
Actinic keratosis: precursor lesions to SCCs
SCC in situ (Bowen's disease): confined to outer layer of skin
Invasive SCC: spread into deeper layers of skin
Metastatic SCC: spread to other parts of body
The following are variants of SCC.
Keratoacanthoma:
Presents as a rapidly growing, dome-shaped nodule with a central keratin-filled crater.
Usually grows over weeks to months and involutes after 2-3 months.
There is debate about the malignant potential of keratoacanthomas, but most dermatologists prefer to excise these tumours, as many consider them to be a well-differentiated variety of SCC.[1][2]
Verrucous carcinoma:
Can be locally destructive but rarely metastasises.
Lesions appear as exophytic, fungating, verrucous nodules, or plaques on skin or mucosa.
Further subdivided based on its location: oral cavity (oral florid papillomatosis or Ackerman's tumour); anogenital region (Buschke-Lowenstein tumour); plantar foot (epithelioma cuniculatum).
Marjolin ulcer:
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