Science of Skin

Basal Cell Carcinoma (BCC)

Snapshot
Other common terms: BCC, BCC skin cancer, non-melanoma skin cancer, NMSC
ICD-10 classification: C44.0
Prevalence: 75% of all skin cancers are basal cell carcinomas. Much higher in fair skinned populations. 1600:100,000 in Australia, 40-80:100,000 in European countries, approx 300:100,000 in USA
Causes: Chronic UV exposure light is believed to play a role, along with genetic predispositions (fair skin, blue/green eyes, red/blonde hair). X-rays, arsenic and coal tar derivatives.
Symptoms: Skin cancer in basal cells of the skin. Generally a bump or skin growth, or it could be flat or slightly raised. Colours may be white or light pink; flesh-coloured or brown; or pearly, or waxy.
Treatments/cures: Surgical excision, Mohs surgery, curettage, cryosurgery
Differential diagnosis: Other skin cancers, particularly squamous cell carcinoma
A basal cell carcinoma
A basal cell carcinoma skin cancer

Basal Cell Carcinoma (BCC) is a form of non-melanoma skin cancer that arises from the cells of the lower (i.e. basal) part of the outer layer of the skin (the epidermis). BCC is a type of non-melanoma skin cancer and is the most common cancer in the world, but is rarely fatal, as the cancer’s ability to invade other tissues and organs is limited. It does, however, cause considerable morbidity in afflicted individuals and places a huge burden on healthcare systems around the world. Moreover, individuals afflicted with BCC have an increased risk of further developing BCC and other malignancies.

Incidence

To accurately describe the frequency of BCC is fraught with problems, because it tends to be under-registered or not registered at all. In white populations in Australia and the rest of the world, the incidence of BCC has doubled every fourteen years. Although the increased incidence can be partly explained by improved diagnostics and increased awareness in seeking medical attention, the extent of the increase suggests that other factors, such as geographical variations and behavioural changes, are important. The age-standardized incidence per 100,000 per year ranges from 40 to 80 in Northern Europe, through about 300 among whites in southern USA to over 1600 in Australia. The age-standardized incidence in white males is greater than white females by 30 - 80%. The age-specific incidence increases after the age of 20, with a majority of sufferers (over 96% in Australia) over 40 years of age. Dark-skinned populations show a much lesser incidence of BCC compared to their white counterparts living in the same climate. Childhood migrants acquire the risk of their adopted country, whilst individuals who migrate in their adult life have a risk midway between those of their country of origin and adopted country in developing BCC.

BCC is the most common form of skin cancer, accounting for around 75% of skin cancers. Australia has the highest rate of BCC incidence in the world. It is estimated that 295,000 Australians (about 1 in 14 individuals) will be diagnosed with BCC in 2008. In 2006, 410 individuals (about 1 in 120 individuals) died of BCC in Australia. Over 96% of afflicted individuals were 40 years of age or older. The incidence of younger Australians with BCC is increasing, however, and this has been attributed to increased sun exposure.

Causes

The following features are associated an increased risk of acquiring BCC:

  • Individuals with a fair-complexion, blue or green eyes, blonde or red hair. Red hair and a light complexion tend to be more strongly associated with BCC than does eye colour. Skin type, with the propensity to burn but never tan, confers a risk of developing BCC.
  • A history of painful episodes of sunburn during childhood.
  • Exposure to X-rays, arsenic and coal tar derivatives.
  • Skin disorders such as albinism and xeroderma pigmentosum.

BCC and Ultraviolet Radiation (UVR)

Cumulative exposure to ultraviolet radiation over a number of years, intriguingly, does not confer a substantial risk in developing BCC. It has been postulated that this could be due a threshold level of sun exposure, beyond which BCC stem cells undergo apoptosis in lieu of undergoing uncontrolled growth.

Sporadic cases of BCC occur as a result of interplay between genes and the environment. Ultraviolet light is a mutagen and generates photoproducts that have been shown to be carcinogenic in mice. A combination of ultraviolet-induced DNA damage and impaired immune modulation are thought to be responsible for carcinogenesis of the skin. PTCH, a tumour-suppressor gene located on chromosome 9, whose protein product acts as a receptor for the Sonic hedgehog protein (shh), appears to be perturbed in BCC, especially in familial BCCs. Binding of the wild-type shh to the protein product of PTCH inhibits another protein, known as Smoothened (smo), resulting in the suppression of cell proliferation. Mutations in the PTCH and SMO genes can relieve this suppression and lead to cell proliferation via downstream transcription factors, such as E2F1. The expression of bcl-2, an inner mitochondrial membrane protein that inhibits apoptosis, has been observed in cases of BCC. Enhanced expression of mutant p53, in the absence of an increase in p21 levels, also seem to occur in some cases of BCC, especially in the aggressive forms of BCC. Mutant p53 variants are thought to be predominantly due to exposure to ultraviolet light. Thus, a combination of uncontrolled proliferation and reduced apoptosis result in oncogenesis of the basal cells. In the more aggressive forms of BCC, matrix metalloproteinases and certain glycoproteins play an important role by releasing proplastic cytokines and inhibiting tumour growth and invasion respectively.

Metastatic BCC

Metastatic BCC is extremely rare, with reported incidence rates of up to 0.55%. Metastatic BCC usually begins as a large, neglected and locally-invasive lesion that is unresponsive to treatment and recurs. The 5-year survival rate for metastatic BCC has been reported at 10%. The selective expression of cytoskeletal microfilaments and actin proteins in invasive BCC subforms, and differential attachment patterns of BCC cells are thought to play a role in metastasis. It is not clear why BCCs have a limited metastatic potential and it has been postulated that interactions between the stroma and neoplastic BCC cells may be the key.

Symptoms

A basal cell carcinoma
Basal cell carcinoma skin cancer

BCC may appear as a bump or skin growth, or it could be flat or slightly raised.
Colours may be white or light pink; flesh-coloured or brown; or pearly, or waxy.

The abrasion may present itself as:

  • A skin sore that bleeds easily or doesn’t heal;
  • Oozing or crusting spots in a sore;
  • A scar-like sore; or
  • A sore with a sunken (depressed) middle.

BCC is usually slow-growing with a limited ability to metastasize. Yet, aggressive forms of the disease have been reported. Growth of BCC is usually localized to the site of origin. Some tumours, however, may invade tissues in a three-dimensional fashion that is difficult to ascertain through visual inspection. If left untreated or under-treated, BCC can invade and destroy local tissue, particularly the ears, eyes and nose. The clinical course of BCC is unpredictable with wide differences in how aggressively the tumour grows. BCC is predominantly found on the head and neck. It can also occur on the trunk and lower limbs. Occurrence in other areas of the body is rare. In recent years, an increase in truncal BCC has been observed, suggesting that the association between UV exposure and BCC may be less direct than with other types of skin cancer.

BCC can arise in the setting of scars, draining sinuses, ulcers, burn sites or at foci of chronic inflammation. BCC can occasionally be accompanied by bleeding, scaly formations or crusting. Aggressive forms of BCC tend to show ulceration and local invasion and destruction. The size of the tumour determines the risk of metastasis and death. Tumours over 3 cm in diameter have a slightly elevated risk of metastasis, whilst tumours over 5 cm in diameter have a substantial risk of metastasising and causing death.

BCC is diagnosed by noting the colour, shape, size and texture of the lesion. A biopsy is performed, if necessary. Two biopsy methods are often employed - shave biopsy or punch biopsy. For shave biopsies, a razor blade that can be precisely manipulated is often superior to a scalpel. A punch biopsy is usually restricted to flat lesions and for recurrent BCC occurring in a scar. Examination of the sample under a microscope will reveal the nature of the BCC, as discussed below.

Based on the morphology of the tumour, BCCs have been classified into four sub-types:

  • Nodular and nodular-ulcerative BCC - This is the most common sub-type, which arises as red-gray pearly nodules (or cysts) with a rolled border, usually on the face. They tend to extend and ulcerate, if untreated.
  • Pigmented BCC - This sub-type exhibits similar morphology to nodular BCC, but there are areas of melanin pigmentation within the tumour. Its morphological appearance may be confused with that of melanoma.
  • Superficial BCC - Usually arises on the trunk, as flat, erythematous plaques, which can mimic other skin disorders, such as psoriasis.
  • Morphoeic BCC - This is the most important clinical sub-type, as it has an aggressive clinical course and presents as a yellow-white scar with ill-defined borders. Therefore, diagnosis and complete excision is often difficult and specialised treatment, such as Moh’s surgery, may be warranted.

BCC increases the risk of developing further BCC and other skin cancers. BCC may also be associated with other malignancies, but the association between BCC and other carcinomas (such as of the lung, thyroid, breast, cervix, mouth and non-Hodgkin’s lymphoma) is unclear and requires further research.

Treatments

Physicians will first examine the suspect spot, noting the colour, shape, size and texture. A biopsy may be performed, if necessary, in which a small section of the lesion is collected and examined under the microscope to determine if it is cancerous. If the spot is cancerous, then either the spot is removed or the cancerous cells are killed. The treatment method undertaken will depend on the size, depth and location of the spot.

A basal cell carcinoma
Basal cell carcinoma skin cancer

Treatment of BCC can involve surgical and non-surgical techniques.
Surgical techniques include:

  • Excision - the cancer is cut out and the skin is stitched back together. An excision margin of 4 mm around the tumour has been recommended, where possible.
  • Mohs micrographic surgery - sections of skin are cut out and are examined under the microscope to check four cancer cells. This process is repeated until there are no more cancer cells left. Offers high cure rates at at-risk sites. This modality is particularly effective in the treatment of recurrent BCC.
  • Curettage / electrodessication - the cancer cells are scraped away and then electricity is used to kill any remaining cells. This procedure does not provide enough tissue sample to examine the borders of the tumour histologically.
  • Cryosurgery (using liquid nitrogen) - freezing the cancer cells to kill them. No tissue sample is available for histological review.

Non-surgical techniques include:

  • Radiotherapy - used in elderly patients with extensive lesions, where surgery is inappropriate. It is not used in young patients, however, due to undesirable cosmetic effects.
  • Topical photodynamic therapy - involves application of a topical, emulsion-based δ-amino-laevulinic acid. Tumour cells, on absorbing this compound, become photosensitive and are subject to photodestruction at wavelengths of 620 - 670 nm. It is used in the treatment of superficial BCC.
  • Other topical treatments - fluorouracil is used in the management of multiple superficial BCC on the trunk and limbs. Another agent, imiquimod - an immunomodulator - is used in the treatment of superficial BCC.

Prevention

Prevention of BCC involves being aware of the causal factors and avoiding them. Genetic and environmental factors play a causative role in the genesis of BCC. Environmental factors are more amenable to control and manipulation. Avoiding ultraviolet exposure is essentially impossible; however, the use of high-protection sunscreen and reducing the exposure to sunlight may help prevent the occurrence of BCC. Educating individuals about the need to be mindful of the dangers of sun exposure and detecting tumours at their early stages will aid in improving clinical outcomes and reducing recurrence of BCC. Individuals should be educated to look out for any suspicious growth or changes in skin colour, texture and appearance, on a regular basis. Seeking medical attention when existing skin sores bleed, itch, swell or inflamed with pain, will also enable early diagnosis and treatment. Regular screening of at-risk individuals may be effective, but is contingent on the availability of healthcare professionals and funding provisions.

Prognosis

The recurrence rate of BCC varies depending on the technique used to treat it. Moh’s surgery offers the lowest recurrence rate at 1%. The use of other treatment modalities results in recurrence rates of up to 10%. Long-term follow-up of treated patients may not always be feasible and it is necessary to educate the patient about avoiding exposure to the sun and to examine the skin for any changes on a regular basis. Regular full-body skin examination and follow-up may be reserved for patients with recurrent BCC or aggressive forms of BCC.

References

  • Bale, A E & Yu, K (2001). ‘The hedgehog pathway and basal cell carcinomas’. Human Molecular Genetics, Vol 10(7), pp. 757-762.
  • Bath-Hextall, F, Bong, J, Perkins, W & Williams, H (2004). ‘Interventions of basal cell carcinomas of the skin: systematic review’. British Medical Journal, Vol 329(7468), pp. 705-709.
  • Crawson, A N (2006). ‘Basal cell carcinoma: biology, morphology and clinical implications’. Modern Pathology, Vol 19, pp. S127-S147.
  • demcoll.edu.au (2015) Basal Cell Carcinoma. [Online]. Available online [Accessed 22/12/2015].
  • Lear, J T, Harvey, I, de Berker, D, Strange, R C & Fryer, A A (1998). ‘Basal Cell Carcinoma’. Journal of the Royal Society of Medicine, Vol 91, pp. 585-588.
  • nlm.nih.gov (2008) Basal Cell Carcinoma. [Online]. Available online [Accessed 24/11/2008].
  • skincancer.gov.au (2008) Basal Cell Carcinoma. [Online]. No longer online [Accessed 24/11/2008].
  • Wong, C S M, Strange, R C & Lear, J T (2003). ‘Basal Cell Carcinoma’. British Medical Journal, Vol 327, pp. 794-798.
  • Woolff, K, Goldsmith, L A, Katz, S I, Gilchrest, B A, Paller, A S & Leffer, D J (2003). ‘Basal Cell Carcinoma’. Fitzpatrick’s Dermatology in General Medicine, 7th ed., Chapter 115. Link no longer online. [Accessed 26/11/2008].

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