The mechanisms by which beta HPV drives this malignant progression are multifaceted. HPV E6 proteins trigger the degradation of BAK, a proapoptotic protein responsible for inducing cell death following UV-induced damage.¹ The loss of this response means that cells carrying extensive DNA damage and oncogenic mutations are able to survive rather than undergo apoptosis. Compounding this, HPV E6 proteins also inhibit the repair of UV-induced damage and double-strand DNA breaks, allowing mutations to accumulate and facilitating malignant progression.¹

HPV E6 proteins further contribute to oncogenesis by inhibiting both NOTCH signalling and TGF-beta signalling, two pathways that ordinarily perform tumor suppressor activities in the skin.¹ The suppression of these pathways therefore removes an additional layer of protection against malignant transformation.

Importantly, HPV can contribute to cancer initiation by starting the oncogenic process, however sustained viral gene expression is not required to maintain the malignant transformed state. Taken together, human papillomavirus is a contributing factor in the development of both basal cell carcinoma and squamous cell carcinoma.¹

The fact that Merkel cell carcinoma is more commonly observed in immunosuppressed patients highlights the critical role the immune system plays in this disease.¹ Merkel Cell Polyomavirus is a common infection, and it is the immune system's failure to adequately control it that represents a key factor in the development of these otherwise rare cancers.

UVA radiation, spanning 315 to 400 nm, consists of the longest wavelengths and is capable of penetrating deep into the skin as far as the epidermal junction where melanocytes are located. It is primarily responsible for premature skin aging.²

UVB radiation, ranging from 280 to 315 nm, carries shorter wavelengths that stimulate increased melanin production and are responsible for the characteristic signs of sunburn, including erythema, oedema, and pain.²

UVC radiation, spanning 100 to 280 nm, represents the shortest and most dangerous wavelengths, though under normal circumstances it is absorbed by the ozone layer and atmosphere before reaching the skin's surface.²

Climate Change Impact

Ultraviolet radiation plays a meaningful role in the development of cancer of the lower limbs. This is illustrated by epidemiological data from Sweden, where the incidence of squamous cell carcinoma of the lower limbs is 1.74 times higher in the southern part of the country compared to the northern part, a difference attributable to the more extensive UV radiation exposure in the south.³

Anatomical distribution of these cancers also reflects patterns of UV exposure. In females, the lateral side of the leg is more frequently affected than the medial side, which is explained by differences in clothing styles between sexes that result in greater UV exposure to the outer surface of the leg compared to males.³

Looking beyond current trends, the depletion of the ozone layer and the expansion of the Antarctic ozone hole are allowing greater amounts of UV radiation to reach the Earth's surface, suggesting that the risk of UV-related skin cancers of the lower limbs is likely to increase as a consequence of climate change.³

The presence of moles represents another important risk factor. Having a high number of pigmented moles or large congenital moles increases the likelihood of melanoma developing either within the skin or within pre-existing moles. There is a consistent and clear relationship between the total number of pigmented moles and the risk of cutaneous malignant melanoma. Notably, the distribution of moles in children closely mirrors the distribution of melanoma in adults, suggesting that strong, intermittent sunlight exposure during childhood serves as a common etiological factor underlying both mole distribution and subsequent cancer development.⁴

Age is also a relevant consideration in non-melanoma skin cancers, with basal cell carcinoma and squamous cell carcinoma occurring most commonly after the fifth decade of life.

Medical and Iatrogenic Factors

Immunosuppression is a well-recognised risk factor for skin cancer, with individuals who have received organ transplants or are living with AIDS/HIV facing a significantly increased risk.² Additionally, certain medical treatments themselves carry carcinogenic potential. Radiotherapy, phototherapy, and PUVA therapy, which combines psoralen with ultraviolet A radiation, are all associated with an increased risk of basal cell carcinoma and squamous cell carcinoma.²

Several treatments historically used for psoriasis, a chronic autoimmune inflammatory condition affecting the joints and skin, have also been implicated in skin cancer development. Arsenic and tar-based treatments represent a major risk factor for squamous cell carcinoma, while X-ray therapy carries well-documented long-term carcinogenic effects.² Dithranol, another agent used in the management of psoriasis, is capable of interacting with DNA, has been shown to cause mutations in yeast, and acts as a potent co-carcinogen in animal models, further highlighting the carcinogenic risk associated with certain therapeutic interventions.²

Malignant Melanoma and Non-Melanoma Skin Cancers

Malignant melanoma is becoming increasingly common in young adults, with intermittent, intense exposure to sunlight representing a major risk factor.⁴ Recreational activities such as boating, sunbathing, and fishing are particularly relevant in this context.⁴ Sun exposure and sunburns occurring during childhood are considered especially harmful, carrying a significant influence on the likelihood of melanoma development later in life.⁴

Regarding non-melanoma skin cancers, the relationship with sun exposure differs somewhat between the two main subtypes. Basal cell carcinoma is more closely associated with a tendency to sunburn, while squamous cell carcinoma is linked to high cumulative sun exposure over time, reflecting the differing ways in which UV radiation drives each distinct cancer type.⁴