© Borgis - Postępy Nauk Medycznych 9/2009, s. 696-705
Tomasz Dębski, Lubomir Lembas, *Józef Jethon
Basal cell carcinoma. Current views (Part I). Epidemiology, pathogenesis, clinical features
Rak podstawnokomórkowy skóry. Współczesne poglądy (Część I). Epidemiologia, patogeneza, obraz kliniczny
Department of Plastic Surgery, The Medical Centre of Postgraduate Education in Warsaw
Head of the Department: Józef Jethon, MD, PhD, Professor of Plastic Surgery
Basal Cell Carcinoma (BCC) is one of the most common human malignancies. Although it is not directly life-threatening and rarely metastasises, its local malignant features cause significant functional and aesthetic disturbances, what has a profound effect on the quality of life of patients.
The constantly increasing incidence of BCC observed within the last couple of years and the fact that this malignancy tends to occur in younger and younger people prove that BCC is now and will be in the future an important clinical problem. However, this problem is undernoticed and underestimated mainly to its low mortality and the fact that this malignancy is not listed in incidence reports.
Although currently several factors are suspected to be responsible for BCC the most important roles in cancerogenesis are played by UV radiation and advanced age of patients. They account for more than 90% of BCC.
Diagnosis of BCC basing only on the clinical appearance is difficult and depends on physician´s experience to a large extent. Traditionally, several clinical forms of BCC can be distinguished; however, the awareness of their existence may only help distinguish oncologically suspicious lesions, and not diagnose them. A histopathological examination is the only test that can verify and complete the BCC diagnosis.
The clinical course of BCC is not characteristic and cannot be predicted: a lesion may not change for years, it may grow slowly or extremely fast, the infiltration area may enlarge or recede, it may also ulcerate or tend to heal. BCC metastases occur extremely rarely (<0.1% of cases).
Rak podstawnokomórkowy skóry (Basal Cell Carcinoma – BCC) jest najczęściej występującym nowotworem złośliwym człowieka. Chociaż nie zagraża on bezpośrednio życiu i rzadko daje przerzuty, jego miejscowa złośliwość jest przyczyną znacznych zaburzeń funkcjonalnych i estetycznych, co istotnie wpływa na jakość życia pacjentów.
Stały wzrost zachorowań na BCC obserwowany w ciągu ostatnich lat oraz tendencja do występowania tego nowotworu u osób coraz młodszych, świadczą o tym, że BCC stanowi i będzie stanowił istotny problem kliniczny w przyszłości. Problem ten jest jednak niedostrzegany i niedoceniany głównie ze względu na niewielką śmiertelność oraz nieuwzględnianie tego nowotworu w zestawieniach zachorowalności.
Chociaż w chwili obecnej postuluje się kilka czynników odpowiedzialnych za powstawanie BCC, najistotniejszą rolę w kancerogenezie odgrywają promieniowanie UV oraz zaawansowany wiek chorych. Odpowiadają one za ponad 90% zmian nowotworowych.
Rozpoznanie BCC na podstawie samego obrazu klinicznego jest trudne i w dużej mierze zależy od doświadczenia badającego. Tradycyjnie wyróżnia się kilka form klinicznych BCC, których znajomość może pomóc jedynie w wyodrębnieniu zmian podejrzanych onkologicznie, a nie w rozpoznaniu. Jedynym badaniem weryfikującym rozpoznanie wstępne i decydującym o rozpoznaniu BCC jest badanie histopatologiczne.
Przebieg kliniczny BCC jest niecharakterystyczny i nieprzewidywalny: zmiana może nie zmieniać się przez lata, rosnąć powoli lub bardzo szybko, zwiększać obszar nacieku lub ustępować, ulegać owrzodzeniu lub nawet goić się. Przerzuty BCC zdarzają się niezwykle rzadko (<0,1% przypadków).
„A surgeon treating neoplasms has to acquire the whole extensive knowledge on neoplasms, their distinctive pathology and natural history as well as the knowledge on rules, methods, techniques, diagnostic and therapeutic possibilities as well as possibilities to work in an oncological team the part of which a surgeon is.”
prof. Tadeusz Koszarowski, the creator of Polish oncology
Neoplastic lesions of the skin are among the most common human malignancies. They originate from different skin tissues and structures such as:
? skin appendages (hair follicles, sebaceous glands, eccrine sweat glands, apocrine sweat glands),
? pigment cells (melanocytes),
? mesenchymal structures (fibrous tissue, fatty tissue, blood and lymphatic vessels, muscles),
? nerves and APUD cells of the neuroendocrine system,
? lymphatic system cells.
The vast majority of neoplasms originating from the above skin structures are benign neoplasms. They are characterised by slow local growth and lack of intensive tissue damage.
The remaining part of neoplastic lesions consists of skin malignancies including carcinomas (originating from the epidermis and skin appendages), melanomas (originating from pigment cells), lymphomas (originating from the lymphatic system cells) and sarcomas (originating from other skin cells) (tab. 1).
Table 1. Classification of skin cancers according to the WHO classification (14).
||Benign neoplasms (examples)
|Non-melanoma skin cancers (97%)
||Melanoma malignum (3%)
|2. Skin appendages:
|• hair follicles
|• sebaceous glands
|• eccrine sweat glands
||primary eccrine carcinomas (e.g. mucous carcinoma) secondary eccrine carcinomas (e.g. malignant cylindroma)
|• apocrine sweat glands
||papillary apocrine adenoma
||apocrine carcinoma Paget´s disease
|3. Pigment cells
|4. Mesenchymal structures:
|• fibrous tissue
||dermatofibrosarcoma protuberans malignant fibrous histiocytoma fibroxanthoma fibrosarcoma
|• vascular tissue
||angiosarcoma Kaposi´s sarcoma
|• fat tissue
|• muscle tissue
|5. Nervous tissue
||neurosarcoma Merkel cell carcinoma
|6. Lymphatic tissue
||granuloma sarcomatodes Sezary´s disease T-cell lymphoma B-cell lymphoma
Other classification of malignancies is as follows:
Non-Melanoma Skin Cancer (NMSC) and Melanoma Malignum (MM.) NMSC include skin cancers (96% of skin malignancies), lymphomas and sarcomas (1% of skin malignancies). The remaining 3% is MM which is characterised by high malignancy and accounts for 75% of all deaths due to skin neoplasms (1, 2).
Despite the fact that there are different classifications available in literature, one thing that does not change is that cancer is the most common histopathological form of malignancies. Almost all skin cancers originate in the epidermis. Cancers arising in the skin appendages constitute a very low per cent. From a histological point of view the epidermis is stratified epithelium with several layers of cells. Depending on an epidermal layer (the basal cell or squamous cell layer) skin cancers are divided into:
? Basal Cell Carcinoma (BCC) originating from the basal cell layer of the epidermis and sheaths of hair follicles. It constitutes 80% of all skin cancers.
? Squamous Cell Carcinoma (SCC) originating from cells in the Malpighi layer and it accounts for 20% of skin cancers (1).
Although both BCC and SCC originate from the epidermis, their biology is completely different and therefore they cannot be discussed together. For that reason the authors of this review have decided to present problems associated only with one of them, namely BCC.
BCC is of the most common human malignancies, and its incidence has been rising within the last decade (3). Although it is not life-threatening, its local malignant features, especially in the area of the face may cause significant functional and aesthetic disturbances what has a profound effect on the quality of life of patients. If BCC is left untreated, it can infiltrate not only adjacent tissues but also bones and even deeper structures like brain (4). Moreover, extremely rare distant metastases of this neoplasm have been described (5).
BCC diagnostics and treatment is managed by physicians of different specialities (dermatologists, plastic surgeons, general surgeons, oncologists, ophthalmologists, ENT specialists, and even general medicine specialists) who promote therapeutic options which are closely related to their specialities and are often controversial. Available literature reports different therapeutic methods including non-invasive techniques such as local application of Imiquimod-containing ointments (6) photodynamic therapy (7), radiation therapy (8), CO2 laser ablation (9),cryosurgery (10), cautery (11) and curettage (12) or surgical excision of a lesion with a margin of clinically normal surrounding tissues (13).
Functional and aesthetic results, treatment efficacy, side effects and effects on the quality of life are different and depend on the method that has been used.
Method selection depends on lesion morphological features and patient´s condition and preferences. The majority of methods to treat BCC described so far may be used only in some, highly selected cases. The only universal method that can be used to treat all cases of BCC is surgical excision with a margin of clinically normal surrounding tissues.
Due to high efficacy of this method, its versatility, good functional and aesthetic results, low risk of complications, availability, low costs, and what is the most important, the ability of postoperative histological assessment of excision completeness, surgical treatment is currently the most common method to treat BCC.
As there is no unanimous algorithm how to manage this condition and as publications casting a new light on the problem of BCC treatment have been published within the last several years the authors of this review have decided to make an attempt to systematise current views on epidemiology, etiopathogenesis, diagnostics and treatment of this neoplasm, with special attention drawn to surgical treatment.
Among all human malignancies skin cancer occurs the most frequently and it accounts for almost 1/3 of all detectable neoplasms (1). Despite the fact that since the early 1990s the global incidence of neoplasms has been decreasing the rate of incidence of skin cancer has been rising and it is estimated to be 10-15% annually, what is almost ten times higher than the population growth rate (1, 15, 16). It has to be emphasised that there are no precise records especially with regard to BCC and therefore epidemiological data are often understated and not included in global lists of incidence rates of neoplasms (1).
Only in the USA, more than one million cases of skin cancers are detected every year (17). It is the number almost equal to the number of all other cancers detected annually in this country (18). It is estimated that one out of five Americans will develop skin cancer (17), and in almost half of 65-year-olds this cancer will occur at least once in their lives (19).
Although the data presented above regard all cases of skin cancers it can be assumed that they reflect BCC epidemiology to a large extent, as BCC accounts for almost 80% of all cases of skin cancers (1).
Global statistics unanimously indicate that BCC is one of the most common neoplasms in Europe, Australia (20) and the USA (21), and the number of new cases is increasing every year (tab. 2).
Table 2. Incidence rate for selected neoplasms based on Globocan 2002 (number of detected cases/year/100 000 citizens) (22).
||Non-melanoma skin cancers (w/m)
||Lung cancer (w/m)
||Colon cancer (w/m)
||Breast cancer (w)
Polish epidemiological data are also alarming despite the fact that they are not complete due to lack of precise records (fig. 1).
Fig. 1. Number of new cancer cases in the period 1999-2005 in Poland (source: Krajowy Rejestr Onkologiczny) (23).
Epidemiology of skin cancer unanimously indicates that it is a significant global problem. However, this problem is not noticed and is underestimated especially because of the fact that mortality related with these neoplasms is low (in the USA 1000-2000 patients/year) (24) and that this neoplasm is not listed in incidence records (data are not complete.) The importance of this problem is mainly affected by the number and dynamics of new cases, a high recurrence rate (even 18%) (25) and generally high costs of treatment (in the USA the costs of treating skin cancers were more than one billion dollars in 2004) (26).
Although currently several factors are suspected to be responsible for BCC the most important roles in cancerogenesis are played by UV radiation and advanced age of patients. They account for more than 90% of neoplastic lesions (27).
Solar radiation (UV) can be divided into three parts depending on the wavelength: UVA (wavelength of 320-400 nm), UVB (wavelength of 280-320 nm) and UVC (wavelength of 200-280 nm) (1).
The majority of radiation emitted by the Sun is absorbed by the ozone layer of the atmosphere, and consequently, only a low amount reaches the Earth. As due to atmosphere pollution the thickness of the ozone layer is gradually reduced, more and more UV radiation reaches the Earth, therefore the incidence of BCCs can increase (28). This phenomenon may also explain the fact that this neoplasm occurs in younger and younger patients as they earlier achieve a cancerogenesis threshold of Average Accumulated Exposure (29).
Exposure to UVB radiation contributes to the BCC development the most (30).
Contrary to common opinions short-term but intensive and long-term but less-intensive exposure are equal (31). The dose of UV absorbed in the childhood does not contribute significantly to neoplasm pathogenesis according to the latest reports (32).
Long-term UVB actions lead to the formation of mutagenic photoproducts that damage DNA chains in skin cells. DNA damaged in this way is repaired within 24 hours as a result of the effective repair system called NER (nucleotide excision repair system) (33). Impairment of this system present in patients with xeroderma pigmentosum inevitably leads to multifocal skin cancer and death at a young age.
Apart from damage to DNA of skin cells UV radiation also causes mutations in a suppressor gene of the p-53 protein. The protein coded by this gene has anti-oncogenic properties as it induces apoptosis in the cells with damaged DNA. As a result of a mutation in this gene the anti-oncogenic properties of the p-53 protein are turned off, therefore the cells with damaged DNA proliferate without control. The presence of a mutation in the p-53 gene is found in 60-100% of cases of skin cancer (34).
The skin inflammatory response induced during the exposure to UV also participates in the process of damaging DNA (35) inducing disturbances of division and mutations in newly produced cells (36).
The sources of UV radiation include not only solar radiation but also PUVA lamps used to treat psoriasis and albinism as well as tanning lamps.
Due to the fact that tanning lamps are widely accessible and due to fashion trends they have become especially important in BCC etiopathogenesis in the last years. Some of these modern tanning lamps may emit radiation doses which are even 12 times higher than the ones emitted by the Sun (37). The risk of BCC in subjects using tanning lamps regularly is twice the risk observed in the general population (38). The significance of solar radiation in BCC pathogenesis is emphasised by the fact that this neoplasm is found on the skin areas with the most exposure to sunlight, such as the head and neck (85% of all lesions, including 30% within the nose (39, 40).
Exposure to some chemicals
It is claimed that such substances as arsenic, wood tar, gas pitch, synthetic antimalarial agents or psoralens participate in BCC cancerogenesis (1).
Age. A peak in the incidence is between 60 and 80 years of age. More than 95% of patients are patients above 65 years old (1) although recently it has been observed that the incidence in the population below 40 years old is growing (29). With age the total period of UV radiation exposure (Average Accumulated Exposure) increases, therefore when a given threshold is exceeded cancerogenesis processes are initiated. Moreover, the reduced immunity and reduced DNA repair and regeneration properties occurring in the elderly also contribute to the increasing incidence of BCC in this age group (41).
Sex. Men slightly more frequently suffer from BCC (M/F ratio 1.2) (42). It is probably associated with higher exposure to UV radiation what is a result of different working conditions (usually outdoors) and rarer use of sun screens in the case of men (43). It should be noted that during the last 30 years the rate of women below 40 years of age suffering from BCC has tripled (2).
Race. People with fair skin type, light blue and grey eyes and with light red and fair hair suffer from BCC more frequently than people with dark skin (43, 44, 45).
Fair hair, frequent sunburn and freckles in the childhood are features which are especially associated with BCC development (46).
Previous BCC treatment. After the first case of BCC in one´s life the probability of the second one increases ten times (47). In 50% of patients with previously diagnosed BCC other foci will form within 5 years since the first manifestation (42). It is estimated that the likelihood of BCC in such patients is almost 140 times higher that the one in the general population (48).
Post-organ transplant patients. In post-organ transplant patients BCC is the most frequent neoplasm and accounts for 35% of all neoplasms occurring in this group of patients. It is estimated that post-organ transplant patients suffer from BCC 65-250 times more frequently than the general population. BCC most frequently occurs in patients after heart and renal transplantation (49).
Higher incidence of BCC in this group is associated with long-term immunosuppressive therapy that reduces the number of CD4 + cells (50).
The pharmacological immunosuppression combined with UVB radiation that additionally reduces the number of Langerhans cells (immune properties) leads to increased immunosuppression in the skin and increases the risk of neoplasm (51).
Leukaemic patients due to immune system dysfunctions are the next group at a risk. BCC most frequently occurs in patients with chronic lymphocytic leukaemia (8-13 times more frequently than in the general population) (52).
Other risk groups. According to recent opinions risk factors that have not been so widely studied include genetic predisposition (53, 54) freckles (55) and rich-fat diet (56) which is low in antioxidants and vitamins (58).
Precancerous lesions are morphologically changed tissues (a pathological process) on the basis of which neoplasm develops more frequently than in other unchanged tissues (1).
BCC most frequently develops in the skin without previous lesions. It can significantly more rarely (contrary to SCC) develop on the basis of precancerous lesions. Precancerous lesions leading to BCC development include:
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