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Basal Cell Carcinoma - Information for Medical Professionals

Definition and Description

Basal cell carcinoma is the most common skin tumor in humans. It develops from basal, undifferentiated epithelial cells of the skin and displays a potential for local invasion and destruction, but it seldom metastasizes.

Clinically it is divided into five major types:

nodulo-ulcerative
pigmented
morpheiform
superficial
solid-cystic

The tumor develops on hair-bearing skin, most frequently on sun-exposed areas. Approximately 85% of basal cell carcinomas are found on the head and neck. More than three quarters of these carcinomas occur in patients over 40, although they may occur at any age from childhood.

Incidence and Epidemiology

Melanoma and nonmelanoma (basal and squamous cell carcinoma) skin cancer are now the most common type of cancer in the Caucasian population and the incidence of skin cancer has reached epidemic proportions. Many epidemiological studies have demonstrated that the incidence of skin cancer has been increasing rapidly over the last decades. Nonmelanoma skin cancers (NMSCs) constitute more than one-third of all cancers in the United States with an estimated incidence of over 600,000 cases per year. NMSCs are the most common malignancies occurring in the Caucasian population each year. Of these 600,000 cases approximately 500,000 are basal cell carcinomas (BCCs) and 100,000 to 150,000 are squamous cell carcinomas (SCCs). The standardized ratio of BCC to SCC is roughly 4 to 1. The incidence of NMSC (BCC and SCC) is 18 times greater than that of malignant melanoma. However, incidence data of high epidemiological quality on NMSC are sparse because traditional cancer registries often exclude NMSC or are at least incomplete. Miller & Weinstock (1994) estimated the 1994 NMSC incidence in the United States to be between 900,000 and 1,200,000. The lifetime risks were estimated to be 28% to 33% for BCC and 7% to 11% for SCC (lifetime risk of developing NMSC for a child born in 1994)

BCC represents 75% of NMSC and is, therefore, the most common malignant disease throughout the world. Silverberg et al (1990) estimated the average annual incidence of BCC in the United States to 191 new lesions per 100,000 white persons According to the estimates (lowest and highest estimated incidence rates) of Miller & Weinstock (1994) the age-adjusted incidence rates per 100,000 whites per year (1994) in the United States were as follows: BCC (men) 407–485, BCC (women) 212–253), SCC (men) 81-136, SCC (women) 26-59). For South Wales (United Kingdom) the age-standardized (world standard population) incidence rates per 100,000 population in 1998 were lower: BCC (men) 127.9, BCC (women) 104.8, SCC (men) 25.2, SCC (women) 8.6 (Holme et al. 2000). Although these incidence rates are high, they do not approach the rates described from Australia. The incidence is 1% to 2% per year (1000 to 2000 per 100,000 per year): Townsville, Australia (Buettner et al. 1998): BCC (male) 2058, BCC (female) 1195, SCC (male) 1332, SCC (female) 755); Nambour, Australia Green et al. 1996): BCC (male) 2074, BCC (female) 1579, SCC (male) 1035, SCC (female) 472.

There is an increased risk of NMSC in whites, especially those who have blue eyes, a fair complexion, sunburn easily, suntan poorly, freckle with sun exposure, have red, blond, or light-brown hair (Celtic ancestry). NMSC is uncommon in blacks, Asians, and Hispanics. There is a higher incidence of BCC in Albino blacks than in normally pigmented blacks. Compared with whites, blacks have a decreased risk of BCC on sun-exposed areas, but the same incidence of BCC on covered skin. In contrast to whites, sunlight does not appear to be an important etiologic factor for SCC in blacks because lesions occur on non-sun-exposed regions of the body. SCC in blacks arise most often on sites of preexisting inflammatory skin conditions, burn injuries, or trauma. SCC in blacks are often seen in scars, burns, or ulcers.

The incidence of NMSC is increasing rapidly. In white populations in Europe, the United States, Canada, and Australia the average increase of NMSC was 3-8%. Chronic sun exposure is the main cause of NMSC. Over 80% of NMSCs occur on areas of the body that are frequently exposed to sunlight, such as head, neck, and back of the hands. BCC is also most commonly found on the nose. The rising incidence rates of NMSC is probably due to a combination of increased sun exposure or exposure to ultraviolet light, increased outdoor activities, changes in clothing style, increased longevity, and ozone depletion. In incidence of NMSC in Caucasians increases proportionally with proximity to the equator, with the incidence of SCC doubling for each 8-10 degree decline in latitude. UV dosage per unit time at the equator in the Pacific is very high, about 200% that of Europe or the northern US, and 30% higher than that of the southern US. The incidence of NMSC is elevated in individuals with a high cumulative exposure to UV light, such as outdoor workers, or those with more frequent outdoor activities. The incidence is also increasing with age: According to Holme et al. (2000) in 1998 the incidence of BCC in individuals over 75 years old was approximately 5 times higher compared to individuals between 50 and 55 years old, and for SCC approximately 35 times higher. The incidence of SCC increases more rapidly with age than does BCC. The reported increases in the incidence of melanoma and NMSC have partially been attributed to a larger amount of UVB radiation reaching the surface of the earth as a result of ozone depletion in the atmosphere. The ozone layer has decreased by approximately 2% over the past 20 years. A 2% decrease in ozone concentration will increase biologically effective radiation from the sun by approximately 4%. It was estimated that this additional UV radiation will cause a 6-12% increase in NMSC in exposed populations.

Once an individual develops a NMSC, there is a 36%-52% chance that a new skin cancer will appear within 5 years.

Etiology and Pathogenesis

The following factors must be considered in the aetiopathogenesis of basal cell carcinoma

Ultraviolet radiation, especially in individuals with fair skin (type I or II)
Chemical carcinogens, especially arsen
Radiotherapy of malignant tumors
Immunosuppression
Genetically determined disorders:

Nevoid basal cell carcinoma syndrome - association of basal cell carcinomas with defects in other tissues
Bazex syndrome - association of basal cell carcinomas with follicular atrophoderma
Xeroderma pigmentosum - defective DNA repair mechanisms lead to excessive chronic UV damage and subsequent development of different sun-related skin tumors in sun-exposed areas

Sebaceous nevus of Jadassohn: basal cell carcinomas as well as other skin tumors may develop in this lesion Although sun exposure seems to be the most important factor, the prevalence and distribution of basal cell carcinoma does not correlate as well with exposure to UV radiation as it has been described for squamous cell carcinoma.

Diagnosis

The clinical appearance is highly variable, as suggested by the different subtypes of basal cell carcinoma. Diagnostic accuracy in the diagnosis of basal cell carcinoma therefore depends on clinical experience. The common nodular type in its initial stages may be hard to differentiate from a melanocytic nevus or senile sebaceous hyperplasia. Darkly pigmented tumors may be confused with malignant melanoma. Ulcerated tumors must be distinguished from squamous cell carcinoma. Superficial basal cell carcinoma has to be differentiated from eczema, psoriasis or Bowen`s disease. The following procedures may prove helpful in finding the right diagnosis.

Debris on the surface should be removed. Scaling or crusting can cause confusion with warts, keratoacanthoma and squamous cell carcinoma. The friable, relatively avascular tissue beneath is characteristic.

When several diagnostic possibilities cannot be ruled out by careful inspection, a biopsy is mandatory.

Symptoms, Signs, and Course

Basal cell carcinoma displays a variety of clinical features, depending on the underlying type of tumor.
Early tumors may present as small, translucent or pearly papules with a few dilated vessels on the surface. Other modes of presentation are as an erythematous plaque, as a keratotic area or as a superficial ulcer.

The nodulo-ulcerative type begins as a small translucent papule with superficial telangiectases and a thread-like margin. In the course of disease, the tumor may grow, and eventually erode, displaying an ulcer in time. The atypical rodent ulcer may begin as a nodule, but more often it is eroded from an early stage. It has an indurated edge and base, the floor of the ulcer being depressed below the skin surface. It may spread deeply and cause great destruction.
The pigmented type also begins as a small papule, but displays a brownish or black color. If it eventually ulcerates, it has to be differentiated from malignant melanoma.
The morpheiform basal cell carcinoma is characterized by a thickened yellowish plaque with a smooth surface, the exact margins of the lesion being impossible to define. This type is uncommon and occurs almost exclusively on the face.
The superficial type presents as a flat, sometimes scaly, erythematous plaque with an often irregular margin. The latter may display a thread-like appearance. This type of basal cell carcinoma is usually found on the trunk and may be mistaken for psoriatic lesions or eczema.
Solid-cystic basal cell carcinomas are relatively uncommon. They present as translucent papules, sometimes with fluctuation. After having been broached, the tumors may drain a serous fluid.

The typical basal cell carcinoma runs a slow progressive course, gradually extending peripherically. If left untreated, though, the tumor may infiltrate cartilage and bone, leading to mutilation, especially of the face and scalp.

Prevention and Prophylaxis

In order to prevent basal cell carcinoma, the risk factors implicated in the pathogenesis of this tumor must be avoided. Important is:

Protection from UV radiation
Avoidance of chemical carcinogens (especially arsen)
Excision of sebaceous nevi is recommended by some authors to prevent the development of secondary tumors

Differential Diagnosis

Nodulo-ulcerative Basal Cell Carcinoma:

Pigmented Basal Cell Carcinoma:

Morpheiform Basal Cell Carcinoma:

Superficial Basal Cell Carcinoma:

Solid-Cystic Basal Cell Carcinoma:

Complications

Basal cell carcinoma may infiltrate surrounding tissue and, if left untreated, may cause great destruction, up to invasion of bone and meninges. Ulceration may occur, either from an early stage in ulcerative basalioma or after some time of growth in other types of basalioma. Eroded and ulcerated tumors are prone to secondary infection. Cases of bloodstream or lymphogen metastasis are very rare (< 0,1%).

Treatment

Several different treatments are used in the management of basal cell carcinoma. Each method may be more or less useful for specific clinical situations.

Surgery

Surgical excision is a highly effective treatment for BCC allowing for histological examination of the excised tissue.
Mohs' micrographic surgery, a method using microscopic control to evaluate the extent of tumor invasion, has the highest cure rate of all surgical treatments. Morpheiform basal cell carcinomas, recurrent tumors, basal cell carcinomas larger than 2 cm in size as well as tumors situated on the ears, lips, nose and nasolabial folds are indications for treatment.

Curettage and electrodessication

Basal cell carcinoma can be scraped away with a curette. Afterwards, electrosurgery may be used to stop bleeding or to apply more damage to the area involved. The adequacy of treatment cannot be assessed immediately since the surgeon cannot visually detect the depth of microscopic tumor invasion. This method should be used only for superficial basal cell carcinomas or small, well defined lesions in non-critical sites..

Cryosurgery

Liquid nitrogen is used to either chill a cryoprobe continuously or to spray on a surface. Individual techniques vary considerably, some clinicians applying up to three freeze/thaw cycles. This technique allows the local destruction of tissue to quite a considerable and calculable depth. It is simple, and complications are rare. However, the successful treatment of basal cell carcinomas requires adequate freezing of the tumor and the margin all round it, which is not always accomplished. Curettage of the tumor immediately prior to cryosurgery may help to increase the cure rate. This method should be used only for superficial basal cell carcinomas or small, well defined lesions in non-critical sites.

Radiotherapy

Radiotherapy includes a range of treatments using different types of equipment. It is best suited for patients of advanced age and poor general health. Radiation therapy can be used to treat many types of basal cell carcinoma, even those overlying bone and cartilage. Very large tumors are often resistant, though, and require radiation doses that closely approach tissue tolerance. Recurrent BCC after a previous radiation therapy prove to be difficult when treated with the same method again.

Topical 5-fluorouracil (5FU)

5-fluorouracil is a cytostatic agent which inhibits several enzymes in tumor cells, through interaction with RNA. It is applied locally in a thin layer and the lesion is subsequently covered with a plastic film. The treatment is repeated daily until the lesion erodes. This therapy may be useful in the management of multiple superficial basal cell carcinomas on the trunk and lower limbs. It cannot be expected to eradicate invasive BCC's.

The technique

PDT is based on the coaction of a photosensitizer, often a porphyrin-derivative, with visible light and oxygen. The photosensitizer specifically accumulates in rapid growing cells (e.g. tumor cells) and is activated by irradiation with visible light. The tumor destruction is caused by the formation of cytotoxic efficient reactive oxygen species, in particular singlet oxygen.

There are several photosenitizer presently in use (porphyrins, porphines, phthalocyanines, etc.) but most of them are not ideal for dermatological indications since they have to be administered systemically and cause general photosensitivity in patients. The most frequent used substance for PDT in dermatology is 5-ALA (d-aminolevulinic acid) and its derivatives. 5-Ala works as a prodrug that is metabolized intracellularly into protoporphyrin IX (PpIX) - the actual photosensitizer. PpIX will, when activated by light, generate singlet oxygen which will cause death of the tumor cells. Besides PDT the photosensitizer can also be activated by Wood light leading to fluorescence of the targeted lesion. In this way tumor lesions can be detected by photo diagnosis (PD).

The use

The standardized procedure for the treatment of AK involves the application of 20% ALA or its ester in a solution or cream. emulsion. 5-ALA then penetrates the skin and is metabolized into PpIX. ALA-uptake is higher by dysplastic cells and PpIX is synthesized more specifically in abnormal cells leading to a higher concentration of PpIX in abnormal than in healthy cells. After an application time of several hours the lesion will be exposed to light of a certain wavelength and intensity.

For irradiation of the lesion there are now several non-coherent light sources in use which differ mainly by their emission spectrum (red light, blue light, green light) and their radiation area.

PDT is not only used for the treatment of actinic keratosis but also seems to be very promising in the treatment of superficial basal cell carcinoma. To penetrate deeper into the skin a red light is used to induce the phototoxic reaction.

Interferon alpha

Treatment of BCC with intralesional Interferon alpha-2 is essentially investigational. The application of this substance intralesionally thrice weekly for a duration of three weeks during a pilot study led to histological evidence of tumor clearance. Studies reported a treatment failure between 20 and 45% 3 months following treatment and a 19% recurrence rate at 1 year. It is an expensive, time-consuming therapy, and long term cure rates are not yet available.

Imiquimod

Imiquimod is a new immune response modifier that induces cytokines including interferons. Applied to basal cell carcinoma topically as a 5% cream during clinical trials, it has proven effective. A treatment duration of several weeks (up to 18 weeks) was necessary, though. Local skin irritation was the predominant adverse effect.

Prognosis

The prognosis quoad vitam is usually good, metastasis being very uncommon in basal cell carcinoma (< 0,1%). If left untreated, basal cell carcinoma may invade cartilage, bone or the orbit, though, and finally arrode main blood vessels causing death. Widely extended tumors may prove difficult to remove, leading to disfigurement.