The Cancer Society of New Zealand has estimated that 50,000 new cases of non-melanoma skin cancer occur in New Zealand each year, by far the most common of all cancers. The most common are basal cell carcinoma and squamous cell carcinoma but because of resource constraints, there is no registration process for these cancers. There were 63 deaths in 1996, nearly all from squamous cell carcinoma, but basal cell carcinoma is much more prevalent. Individuals with multiple tumours are common.
Other malignant tumours of the skin and its appendages are rare. They include eccrine, apocrine and hair follicle tumours, vascular tumours (Kaposi's and angiosarcoma), the neuroendocrine tumour Merkel cell carcinoma, and malignant fibrous histiocytoma. Immune cell proliferative diseases include histiocytosis X and cutaneous T-cell lymphoma.
Ultraviolet (UV) radiation is the main environmental hazard. Direct damage to DNA and immune suppression contribute to a high risk of all forms of skin cancer in outdoor workers, particularly in shorter latitudes. Although considerable damage may occur in childhood, UV exposure throughout life is hazardous.
Human papillomavirus appears to promote skin cancers in immune suppressed patients but probably is not responsible for the majority of skin cancers in the non-immune suppressed population. Other factors responsible for occasional cases of skin cancer include exposure to arsenic, tar (smoking, occupational exposure and therapeutic coal tar), ionising radiation, chronic inflammation (lupus erythematosus, lichen planus etc) and thermal burns.
Some populations are at significantly greater risk of developing non-melanocytic skin cancers, especially basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Genetic traits predisposing to skin cancer include:
Immunosuppression results in a greater number of cancers and more aggressive tumours, most often observed in organ transplant patients on long term azathioprine and ciclosporin.
The risk of skin cancer increases with age, partly explained by increasing number of cellular mutations. Tumours arise because of irreversible genetic changes within a single cell, leading to increased and disordered cellular proliferation and reduced apoptosis (regulated cell death).
Carcinogenesis involves several steps. These may include:
At least some families with melanoma manifest defects in cell cycle control and mutations in CDKN2A, INK4A. Gorlin syndrome is associated with defects in control of proliferation/differentiation and PTCH gene mutations. Xeroderma pigmentosum is due to various mutations in nucleotide excision repair genes and results in skin cancers at an early age.
Intermittent sunburn appears to be most important in the pathogenesis of BCC. There is no precursor lesion for BCC. BCC only arises where there are hair follicles, and is more common in sites where there are many follicles such as the nose.
BCC grow indefinitely and spontaneous regression is uncommon. Nodular and superficial BCCs do not become aggressive and almost never metastasise. Morphoeic/sclerosing BCC is more aggressive but also does not progress to metastatic disease for unknown reasons, perhaps because it is dependent on connective tissue stroma (fibroblasts and collagen fibres). Local invasion may be explained by increased expression of proteinases that degrade surrounding dermal tissue.
BCC probably starts off as a monoclonal differentiation following gene mutation, but further mutations in different parts of the tumour may result in subclones. PTCH gene alterations arise in two thirds of BCCs, p53 mutations in half, and less often mutations at other loci including ras oncogenes. Deletions in chromosome 9q are occasionally observed. BCCs have high telomerase activity and may be associated with decreased repair of UV-induced DNA damage.
Aggressive perineural spread may very rarely result in metastates to lymph nodes, lung and bone. However some reported metastatic BCCs were probably unrecognised poorly differentiated SCC.
In contrast to BCC, cumulative sun exposure is the greatest risks factor for SCC. Chemical agents are more likely to be associated with SCC than with BCC. SCC has precursor lesions, progressively becomes more invasive and aggressive, and may metastasise. SCC can arise from skin and other sites lined by squamous epithelia i.e. mouth, oesophagus and vagina, or from squamous metaplasia arising in lungs or cervix. Cutaneous SCC is much less aggressive than mucosal SCC (lips, genitals and perianal tumours), which have a 30% risk of metastasis to regional lymph nodes and elsewhere.
The precursor lesions, actinic keratoses, arise in sun damaged skin and histologically show dysplastic keratinocytes in the lower epidermis. There is full thickness dysplasia in in-situ SCC (Bowen disease), which is more likely to progress to invasive disease than the actinic keratosis. Tumour initiating and promoting factors are required; ultraviolet radiation has both properties. In vitro and animal data also strongly suggest a role for cyclooxygenase-2 in the formation of actinic keratoses and squamous cell carcinomas.
SCCs are described according to their degree of differentiation. More differentiated tumours are more keratinised (scaly or horny) and invade surrounding tissue by growing into the dermis. The cell of origin of poorly differentiated or anaplastic tumours may be difficult to identify; the pathologist may use anti-keratin antibodies to do so. SCC is not dependent on its stroma so may grow at sites distant from its origin.
SCC commences as monoclonal differentiation within a keratinocyte and then proceeds to experience further genetic mutations in p53, CDKN2A, PTCH, ras and other genes. Deletions in several chromosomes are frequently observed.
The keratoacanthoma resembles a well-differentiated SCC, clinically and microscopically. Similar gene mutations have been described in this tumour, which is biologically benign resulting in spontaneous resolution.
General population screening is an unproven public health measure and is not recommended by the cancer societies in Australia and New Zealand. However, it is generally agreed that medical practitioners should attempt to identify patients at high risk of skin cancer:
Skin cancer examinations may also be offered at special ‘skin check’ days offered to specific industries or the general public. Their value is somewhat controversial. Initial screening may be undertaken by family members, hairdressers, beauticians, nurses, specialist nurses, general practitioners and other health workers.
Commercial mole mapping enterprises utilise dermoscopy and the either the skills of experienced consultant dermatologists or automated diagnosis. They are particularly suitable for on-going surveillance of high risk individuals with many naevi, or to clarify the nature of suspicious melanocytic lesions. Non-melanocytic skin cancers may also be identified.
Education to increase the general public's awareness of skin cancer and the dangers of skin cancer should include:
Patients should be encouraged to present if they have distinctive skin lesions, particularly if they notice growth, change, crusting or bleeding.
Measures to reduce the incidence of skin cancer (primary prevention) may be through governmental or non-governmental health or educational individuals or organisations. The main aims are to reduce sun seeking behaviour and overall exposure of skin and eyes to ultraviolet radiation. The New Zealand sun safety programme is undertaken by the SunSmart Partnership (Cancer Society of New Zealand and Health Sponsorship Council).
Education may include:
Actions can include:
Compliance issues to be considered include:
There is considerable concern and some evidence that effective sunscreens allow people to spend longer in the sun, increasing the overall risk of skin cancer (particularly melanoma). Staying out of the sun and wearing protective clothing should be emphasised.
Chemoprevention refers to the use of pharmacologic agents that inhibit or reverse the process of photoaging or carcinogenesis. Although not yet in common use, chemoprevention may be a realistic measure for many patients.
Potential chemopreventive agents include:
The role of dietary factors in the development of skin cancer is at this time uncertain. Chemoprevention of skin cancer by consumption of naturally occurring botanicals is an attractive proposition. Micronutrients can act as UV absorbers, as antioxidants, or can modulate signaling pathways.
Dietary protection may be provided by carotenoids, tocopherols, ascorbate, flavonoids, or n-3 polyunsaturated fatty acids. Phenolic antioxidants are found in many fruit, vegetables and herbs such as New Zealand puha, olives (lupeol), spinach (lutein and beta-carotene), blueberries (anthocyanins), tomatoes (lycopene), green tea (epigallocatechin-3-gallate) and milk thistle (silymarin). The mechanisms of action of n-3 polyunsaturated fatty acids appear to depend on their anti-inflammatory properties, acting to reduce the u.v.-induced release of cytokines and other mediators from a variety of skin cell types. Oral ingestion of the fern extract Polypodium leucotomas reduces sunburn and photoxicity and may potentially protect against UV-induced DNA damage. This is available as a dietary supplement.
Oral retinoids such as isotretinoin and acitretin reduce the number of skin cancers arising in high risk individuals in which their adverse effects can be justified. They are commonly prescribed for patients who have multiple skin cancers, particularly in the setting of organ transplantation.
Lipid lowering statins and fibrates have compelling data for long-term safety and some clinical evidence for efficacy in the prevention of melanoma and perhaps other skin cancers. Lovastatin and gemfibrozil have been associated with a decreased incidence of melanoma in large, prospective, randomised, double-blind, placebo-controlled clinical cardiology trials. They inhibit the ras and rho genes.
Cox-II inhibitors have recently been demonstrated to be effective at chemoprevention of UV carcinogenesis, but during 2005/5 their use has been restricted due to adverse cardiac effects. Experimentally, topical difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, suppresses increased polyamine synthesis and inhibits tumors in models of skin carcinogenesis. Many other agents that may prove useful for chemoprevention of skin cancer are under investigation in laboratory and clinical studies.
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