tend to acquire the incidence rate of the population they join, whereas those migrating in adult life show a skin cancer riskmidway between those of their adopted ...
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Basal cell carcinoma J T Lear MD MRCP(UK)
Harvey PhD1
D de Berker MRCP(UK)
R C Strange PhD2
A A Fryer PhD2
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J R Soc Med 1998;91:585-588
Basal cell carcinoma (BCC) is the commonest human cancer1, and its incidence is increasing world-wide. Mortality is low but morbidity can be considerable. In this review we discuss the epidemiology, molecular genetics, clinical features and treatment with emphasis on the role of ultraviolet radiation (UV), molecular genetics, new treatment modalities and prevention.
not generally a sun-exposed part of the body these observations have prompted suggestions that the relation between BCC and UV exposure may be less direct than that between squamous cell carcinoma and UV9. The intermittent nature of exposure and systemic immunosuppressive effects of UV are among explanations that have been
DESCRIPTIVE EPIDEMIOLOGY Time, place and person
ANALYTICAL EPIDEMIOLOGY Phenotypic risk factors In BCC, red hair and light skin colour emerge more strongly as independent risk factors than does eye colour9. The adjusted odds ratio for red versus black hair is typically between 2 and 4. Skin type the dynamic tanning or burning reaction to the sun is a clear risk factor, with typical adjusted relative risks for those who burn but never tan of between 2 and 57. A history of painful episodes of sunburn in childhood also raises BCC risk almost threefold10.
To describe the frequency of BCC is not straightforward because many cancer registers do not record it2; and, even when they do, it tends to be under-registered3. In white populations in Europe, North America and Australia, agestandardized BCC incidence rates have doubled about every 14 years4. Although the figures may be inflated by improved ascertainment and a greater willingness to seek medical attention5, there is little doubt that part of this increase is real. Striking geographical variations in BCC incidence are apparent; age standardized rates per 105 per year typically range from 40 to 80 in Northern Europe, through about 300 among whites in the southern USA to over 1600 in Australia6. The age-standardized incidence in white populations is generally higher in males than in females, by 30-80%7. Sporadic BCC is rarely seen before the age of 20 years but thereafter the age-specific incidence increases4. Darkskinned races show much lower incidences than white populations living in the same climate. Childhood migrants tend to acquire the incidence rate of the population they join, whereas those migrating in adult life show a skin cancer risk midway between those of their adopted country and their country of origin. Anatomical distribution Most tumours occur on the head and neck, and particularly on the upper central part of the face. 15-43% of BCCs occur on the trunk. The incidence of truncal BCC is rising more sharply than that for other sites4. Since the trunk is Department of Dermatology, Clinic 6, Bristol Royal Infirmary, Bristol BS2 8HW, UK; 'Department of Social Medicine, University of Bristol, Canynge Hall, Bristol BS8 2PR, UK; 2Centre for Pathology and Molecular Medicine, Keele University,
Staffordshire, UK Correspondence to: Dr J T Lear
suggested.
Environmental risk factors/predisposing factors The direct epidemiological evidence linking cumulative sun exposure and BCC is surprisingly weak7. Well conducted studies, case-control and cohort, have not identified a significant association between estimated cumulative sun exposure and the presence of BCC, when other variables were controlled for9. The association with squamous cell carcinoma is much stronger1 1. The notion that intermittent rather than cumulative UV exposure is important in BCC has received only limited support. Also postulated is a threshold level of sun exposure beyond which the burden of genetic damage in BCC stem cells causes cell death rather than tumour induction. Other non-UV environmental exposures that have been associated with increased BCC risk include ionizing radiation12, high dietary energy intake (especially fat), low vitamin intake and various chemicals and dusts13. Arsenic exposure predisposes to multiple BCC, particularly the superficial type on the trunk. Smoking does not increase BCC risk (unlike that of squamous cell carcinoma) nor, apparently, does the UV emitted by sunlamps or fluorescent lighting, unless exposure is combined with oral psoralen, as in PUVA therapy for psoriasis, when the risk of BCC increases modestly14 if at all. PUVA therapy and therapeutic
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immunosuppression raise squamous cell carcinoma rates much more sharply than BCC rates. Rare syndromes associated with increased risk of BCC and/or squamous cell carcinoma include albinism and xeroderma pigmentosum. In the autosomal dominant condition Gorlin's syndrome milia, circular pits on the hands and feet, dental cysts, spina bifida, syndactyly and cataracts can be associated at an early age ( < 30 years) with multiple BCC. Molecular genetics
Sporadic BCC development probably results from a complex interaction between many genes and the environment. UV is mutagenic in mammalian cells, generates photoproducts such as cyclodipyrimidine dimers (T/T) and is carcinogenic in micel5. A relation was found between reduced capacity to repair DNA and skin cancer risk in xeroderma pigmentosum patients16. More recently, decreased DNA repair and susceptibility to sporadic BCC has been described17. Since exposure to UV constitutes an oxidative stress in skin, the detoxification of these species and their products may be important, and genes involved in the detoxification may be susceptibility candidates. For example, the role of polymorphism in members of the glutathione S-transferase supergene family has been investigated18-20. Thus, allelic variants seem to influence total BCC number, rate of appearance and tumour site. UV can produce a degree of immunosuppression which may be relevant to tumour progression. Much research has concentrated on UVinduced immunosuppression of contact hypersensitivity21. Thus, UV-induced DNA alterations as well as immune modulation may be important in cutaneous carcinogenesis. A high frequency of chromosome 9 allele loss (60%) in BCC tissue suggests that this area contains important BCC tumour suppressor genes22. Recently, PTC, a strong candidate gene for Gorlin's syndrome, has been identified23. This is a human homologue of a drosophila gene (patched), encoding a protein with effects on cell death, proliferation and differentiation. Heritable mutations in this gene have been identified in families with Gorlin's syndrome23. Mutations have also been described in sporadic BCC24. PTC inactivation may be essential for BCC development although its exact role is so far unclear. Clinical features
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Early BCCs are translucent or pearly, with raised areas through which dilated vessels may show. As they advance, various patterns are seen, sometimes making classification difficult. These include nodulo-ulcerative (rodent ulcer), morphoeic, superficial, pigmented, and keloidal variants. Rarely, flesh coloured sessile premalignant fibroepithelio-
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(Pinkus tumour). Telangiectases are characteristically seen, especially in the morphoeic variety. The superficial type is mainly truncal. Morphoeic tumours have a more aggressive natural history and ill-defined margins, so that complete excision under direct vision can be difficult. Typical BCCs are indolent and slowly progressive. Size may fluctuate spontaneously. Clinical diagnosis is validated by histological examination of biopsy specimens. Differential diagnosis includes squamous cell carcinoma, eczema, psoriasis, melanoma, seborrhoeic warts, solar keratosis, sebaceous hyperplasia, molluscum contagiosum, Bowen's disease, appendygeal tumours and granulomatous reactions (e.g. sarcoid). Patients with BCC are at high risk of getting further primary BCCs25. The likelihood depends on the number of lesions present. Thus, in people with one lesion the 5-year risk is 27%, in those with ten or more it is 90%. Male gender, age over 60 years, truncal site and polymorphism in detoxifying enzyme genes also influence risk.20'25 Patients with BCC are also at increased risk of squamous cell carcinoma (relative risk 3-6) and malignant melanoma (217)26. The association of BCC with internal malignancy remains unclear; some studies suggest a small increase in risk of cancer of the lung, thyroid and cervix26'27 and nonHodgkin lymphoma27. If these increases are real, the explanation might lie in exposure to carcinogens such as UV and arsenic. Metastatic BCC is rare, with reported incidence rates ranging from 0.0028% to 0.55%. The typical metastatic tumour begins as a neglected large, ulcerated locally invasive neoplasm that recurs despite repeated treatment28. The average age of onset is 48 years29. The interval from onset to metastasis ranged in one study from 1 to 45 years, with a median of 9, and 5-year survival of 10%. Why BCCs metastasize so rarely is unclear but the dependence of BCC on its stroma is doubtless a factor. mata arise
TREATMENT common treatment for BCC is surgical excision. In a survey of British dermatologists, excision was employed in 58%, curettage and cautery in 24%, and cryosurgery and radiotherapy in 8% each.30 In a Danish dermatology clinic, curettage was the preferred treatment3l. Treatment by non-dermatological surgical specialists, is almost exclusively excision. Excision technique varies according to how the tissue will be submitted for histological examination. Mohs micrographic surgery popular in affluent countries for the treatment of BCCs on the central face, morphoeic BCCs and recurrent tumours relies upon orientation of the specimen to allow histological examination of 100% of the excision margin. Serial excisions are done until the tumour is cleared. By certainty of excision,
The most
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micrographic surgery allows tumour removal by a smaller margin whilst ensuring a cure rate of up to 99%. 32 The proposal that BCCs at all sites be excised by the Mohs technique seems excessive in view of the 99% 5-year cure rate obtainable with the routine techniques. When excision is incomplete, the recurrence rate is 30%. Other forms of treatment provide no histological material and their adequacy and effectiveness must be judged from cure rate alone. Radiotherapy, cryosurgery and curettage with cautery leave wounds that may take 6 weeks to heal. Whilst dosimetry for radiotherapy is relatively standardized, cryosurgery and curettage techniques vary between clinicians. In the best hands, 5-year cure rates of all three modalities are in the order of 95% (for cryosurgery this means double freeze-thaw cycles)33. Radiotherapy is usually advocated for large tumours in older patients, but fractionation of therapy over three or more visits has considerable resource implications. Cryosurgery is particularly suitable for superficial tumours on the trunk and can achieve a 92% 5-year cure rate on eyelid tumours with little damage to subcutaneous structures34. Curettage is usually combined with cautery. The cure rate is increased if the cycle of curetting and cautery is repeated three times within the same procedure and tumours around the nose and ears are avoided35. The common experience of high relapse rate with curettage may stem partly from insufficiently aggressive treatment at the outset. Photodynamic therapy and carbon dioxide laser are further forms of destructive therapy that are currently evolving. Photodynamic therapy relies on percutaneous delivery of delta-aminolaevulinic acid applied under occlusion to the treatment area in a 20% emulsion. Tissues absorbing this porphyrin metabolite become photosensitive with its conversion to protoporphyrin IX and undergo photodestruction when exposed to light in the 620-670 nm range. Treatment success relies upon tissue uptake and light penetration; for superficial BCCs success rates of 92-100% have been recorded35 but rates for nodular tumours are lower36. Follow-up statistics are limited. Interferon-a2b and 5-fluorouracil are local chemotherapeutic agents that have been used experimentally. In a series of 140 patients with BCC treated with intralesional and perilesional interferonoc2b, 67% achieved complete cure, sustained over a mean follow-up of 3 years37. This agent has also been used in Gorlin's syndrome, and seems most useful for early papular lesions38. 5-fluorouracil/adrenalin gel yielded histological tumour eradication in 91% of tumours; the 5-year cure rate is yet to be established39. PREVENTION/FOLLOW-UP
Ideas about BCC prevention are based mainly on the understanding of causal factors and how to avoid them. The
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major aetiological agents in BCC development are genes and the environment. In the latter category, UV is most amenable to manipulation, notwithstanding uncertainties regarding the precise relation between UV exposure and BCC risk. There is some evidence that exposure to sunshine is more pathogenic in childhood than later in life and mathematical models suggest that diligent use of a factor- 15 sunscreen in the first 18 years of life might reduce the lifetime incidence of non-melanoma skin cancer in an individual by 78%40. However, placebo-controlled trials of sunblock in an at-risk group over 2 years did not show any reduction in non-melanoma skin cancer incidence, although non-malignant actinic damage was decreased4l. A big unanswered question in skin cancer prevention is whether sun-screens block out the carcinogenic element of UV42. Other aspects of BCC prevention include patient education on sun avoidance and detection of early tumours when they are easy to treat and less likely to recur. There are primary care42 and community screening initiatives with these aims43. Regular total cutaneous examinations have been advocated as a useful, non-invasive, quick technique to detect new tumours in at-risk individuals.4 However, the most convincing event motivating the patient to self examination and sun awareness is the development of the first skin cancer. Specific chemoprevention of BCC has been studied with long-term low-dose isotretinoin, acitretin and beta carotene. Isotretinoin afforded more side effects than benefit45. Acitretin has been used mainly in renal transplant patients, where it reduces squamous dysplasia more than BCC46. A large placebo-controlled trial of beta carotene in non-melanoma skin cancer did not show any reduction in new skin cancers over a 5-year period47. There is no consensus on the best follow-up regimen for BCC. In the UK, with its small number of dermatologists, the best approach may be to assess the benefits or otherwise of follow-up in high-risk subgroups.
Acknowledgment We gratefully acknowledge the support of the Cancer Research Campaign. REFERENCES I Miller SJ. Aetiology and pathogenesis of basal cell carcinoma. Clin Dermatol 1995;13:527-36 2 Harvey I, Frankel S, Marks R, Shalom D, Nolan-Farrell M. Nonmelanoma skin cancer and solar keratoses II: analytical results of the South Wales skin cancer study. BrJ Cancer 1996;74:1308-12 3 Harvey I, Frankel S, Marks R, Shalom D, Nolan-Farrell M. Nonmelanoma skin cancer and solar keratoses. I. Methods and descriptive results of the South Wales skin cancer study. Br J Cancer 1996;74: 1302-7 4 Levi F, la Vecchia C, Te V-C, Mezzanotte G. Descriptive epidemiology of skin cancer in the Swiss canton of Vaud. IntJ Cancer 1988;42:811-16 5 Green A. Changing patterns in incidence of non-melanoma skin cancer. Epith Cell Biol 1992;1 :47-51
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6 Marks R, Jolley D, Dorevitch AP, Selwood T. The incidence of nonmelanocytic skin cancers in an Australian population: results of a fiveyear prospective study. Med J Aust 1989; 150:475-8 7 Kricker A, Armstrong BK, English DR. Sun exposure and nonmelanocytic skin cancer. Cancer Causes Control 1994;5(4):367-92 8 Marks R, Jolley D, Lectsas S, Foley P. The role of childhood exposure to sunlight in the development of solar keratoses and non-melanocytic skin cancer. Med J Aust 1990; 152:62-6 9 Vitasa BC, Taylor HR, Strickland PT, et al. Association of nonmelanoma skin cancer and actinic keratosis with cumulative solar ultraviolet exposure in Maryland watermen. Cancer 1990;65:2811-17 10 Gallagher RP, Hill GB, Bajdik CD, et al. Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol 1995;131(2):157-63 11 Marks R. Squamous cell carcinoma. Lancet 1996;347:735-8 12 Yamada M, Kodama K, Fujita S, et al. Prevalence of skin neoplasms among the atomic bomb survivors. Radiat Res 1996;146:223-6 13 Gallagher RP, Bajdik CD, Fincham S, Hill GB, Keefe AR, Coldman A, McLean DL. Chemical exposures, medical history and risk of squamous and basal cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev 1996;5:419-24 14 Stern RS, Lange R. Non-melanoma skin cancer occurring in patients treated with PUVA five to ten years after first treatment. J Invest Dermatol 1988;91 :120-4 15 Strickland PT. Photocarcinogenesis by near-ultraviolet (UVA) radiation in Sencar mice. J Invest Dermatol 1986;87:272-5 16 Cleaver JE. Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective. Proc Natl Acad Sci USA 1969;63:428-35 17 Wei Q, Mutanoski GM, Farmer ER, Hedayati MA and Grossman L. DNA repair related to multiple skin cancers and drug use. Cancer Res
1994;54:437-40 18 Lear JT, Heagerty AHM, Smith A, et al. Multiple cutaneous basal cell carcinomas: glutathione S-transferase (GSTM1, GSTTI) and cytochrome P450 (CYP2D6, CYPlAl) polymorphisms influence tumour numbers and accrual. Carcinogenesis 1996;17:1891-6 19 Lear JT, Smith AG, Bowers B, et al. Truncal tumour site is associated with high risk of multiple cutaneous basal cell carcinoma and is influenced by glutathione S-transferase, GSTTI and cytochrome P450, CYPlAl genotypes and their interactions.J Invest Dermatol 1997;108:519-22 20 Lear JT, Heagerty AHM, Smith A, Bowers B, Jones PW, Gilford J, et al. Truncal site and detoxifying enzyme polymorphisms significantly reduce time to presentation of next cutaneous basal cell carcinoma. Carcinogenesis 1997;18:1499-503 21 Streilein JW. Sunlight and skin-associated lymphoid tissues (SALT): If UVB is the trigger and TNF-alpha is its mediator, what is the message? J Invest Dermatol 1993;100:47S-52S 22 Gailani MR, Bale SJ, Leffell DJ, et al. Developmental defects in Gorlin's syndrome related to putative tumour suppressor gene on chromosome 9. Cell 1992;69:111-17 23 Hahn H, Wicking C, Zaphiropoulos PG, et al. Mutations of the human homologue of drosophila patched in the naevoid basal cell carcinoma syndrome. Cell 1996;85:841-51 24 Gailani MR, Stahle-Backdahl M, Leffell DJ, et al. The role of the human homologue of drosophila patched in sporadic basal cell carcinomas. Nature Genet 1996;14:78-81 25 Karagas MR, for the Skin Cancer Prevention Study Group. Occurrence of cutaneous basal cell and squamous cell malignancies among those with a prior history of skin cancer. J Invest Dermatol 1994;102: 1OS-13S 26 Lindelhof B, Sigurgeirsson B, Wallberg P, Eklund G. Occurrence of other malignancies in 1973 patients with basal cell carcinoma. J Am Acad Dermatol 1991 ; 25: 245-8
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27 Frisch M, Hjalgrim H, Olsen J, Melbye M. Risk for subsequent cancer after diagnosis of basal cell carcinoma. Ann Intern Med 1996; 125:815-21 28 Amonette RA, Salasche SJ, Chesney TM, Clarendon CC. Metastatic basal cell carcinoma. J Dermatol Surg Oncol 1981;7:397-400 29 Lo JS, Snow SN, Reizner GT, Mohs FE, Larson PO, Hruza GJ. Metastatic basal cell carcinoma: report of twelve cases with a review of the literature. J Am Acad Dermatol 1991;24:715-19 30 Motley RJ, Gould DJ, Douglas WS, Simpson NB. Treatment of basal cell carcinoma by dermatologists in the United Kingdom. BrJ Dermatol 1 995; 132:437-40 31 Veien SK, Veien NK, Hattel T, Laurberg G. Results of treatment of non-melanoma skin cancer in a dermatologic practice. A prospective study. Ugeskr Laeg 1996;158:7213-15 32 Mak AS, Poon AM, Leung CY, et al. Audit of basal cell carcinoma in Princess Margaret Hospital, Hong Kong: usefulness of frozen section examination in surgical treatment. ScandJ Plast Reconstr Surg Hand Surg 1995;29: 149-52 33 Mallon E, Dawber R. Cryosurgery in the treatment of basal cell carcinoma: assessment of one and two freeze-thaw cycles. Dermatol 1996;22:854-8 34 Tuppurainen K. Cryotherapy for eyelid and periocular basal cell carcinomas: outcome in 166 cases over an 8 year period. Graefes Arch Clin Exp Ophthalmol 1995;233:205-8 35 Salasche SJ. Status of curettage and desiccation in the treatment of primary basal cell carcinoma. i Am Acad Dermatol 1984; 10:285-7 36 Calzavara-Pinton PG. Repetitive photodynamic therapy with topical delta-aminolaevulinic acid as an appropriate approach to the routine treatment of superficial non-melanoma skin tumours. J Photochem Photobiol B 1995;29:53-7 37 Chimenti S, Peris K, Di Cristofaro S, et al. Use of recombinant interferon alfa-2b in the treatment of basal cell carcinoma. Dermatology
1995;190:214-17 38 Kopera D, Cerroni L, Fink-Puches R, Kerl H. Different treatment modalities for the management of a patient with the naevoid basal cell carcinoma syndrome. J Am Acad Dermatol 1996;34:937-9 39 Miller BH, Shavin JS, Cognetta A, et al. Non-surgical treatment of basal cell carcinomas with intralesional 5-fluorouracil/epinephrine injectable gel. J Am Acad Dermatol 1997;36:72-7 40 Stern RS, Weinstein MC, Bake SG. Risk of non-melanoma skin cancer with childhood sunscreen use. Arch Dermatol 1986;122:537-45 41 Naylor MF, Boyd A, Cameron GS, et al. High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol 1995;131:170-5 42 Jackson A. Prevention, early detection and team management of skin cancer: contribution to the Health of the Nation objectives. Br J Gen Pract 1995;45:97-101 43 Rhodes AR. Public education and cancer of the skin. What do people need to know about melanoma and non-melanoma skin cancer? Cancer 1995;75(suppl 2):613-36 44 Lookingbill DP. Yield from a complete skin examination: findings in 1157 new dermatology patients. J Am Acad Dermatol 1988;18:31-7 45 Tangrea JA, Edwards BK, Taylor PR et al. Long term therapy with low-dose isotretinoin for prevention of basal carcinoma: a multicentre clinical trial. Isotretinoin-basal cell carcinoma study group. J Nat] Cancer Inst 1992;84:328-32 46 Bavinck JN, Tieben LM, Van der Woude Fj, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995;13:1933-8 47 Greenberg ER, Baron JA, Stukel TA, et al. A clinical trial of beta carotene to prevent basal cell and squamous cell cancers of the skin. N Engi J Med 1990;323:789-95
